MODIFIED PEPTIDES AND THEIR USE

Abstract

The invention relates to a compound of formula (A) wherein n is an integer from 1 to 6, and R.sub.1, R.sub.1′, R.sub.2, R.sub.2′, R.sub.3, R.sub.3′ are cationic or hydrophobic residues.

##STR00001##

Claims

1-11. (canceled)

12. A compound of formula A: ##STR00071## wherein n is an integer from 1 to 6, wherein R.sub.1 and R.sub.1′ are both either cationic residues or hydrophobic residues, the residues being identical or different wherein R.sub.2 and R.sub.2′ are both either cationic residues or hydrophobic residues, the residues being identical or different; and wherein R.sub.3 and R.sub.3′ are both either cationic residues or hydrophobic residues, the residues being identical or different; wherein when simultaneously R.sub.1 and R.sub.1′ are cationic residues, then R.sub.2, R.sub.2′, R.sub.3 and R.sub.3′ are hydrophobic residues; when two simultaneously R.sub.2 and R.sub.2′ are cationic residues, then R.sub.1, R.sub.1′, R.sub.3 and R.sub.3′ are hydrophobic residues; and when two simultaneously R.sub.3 and R.sub.3′ are cationic residues, then R.sub.1, R.sub.1′, R.sub.2 and R.sub.2′ are hydrophobic residues, or a salt or a solvate thereof.

13. The compound according to claim 12, wherein the hydrophobic residues are chosen from the group consisting of: C.sub.1-C.sub.16 linear, branched or cyclic alkyl and C.sub.4-C.sub.16 aryl or arylalkyl, substituted of not, branched or not, or C.sub.4-C.sub.16 heteroaryl, or heteroarylaklyl substituted of not, branched or not.

14. The compound according to claim 12, wherein the cationic residue is a (CH.sub.2).sub.m—R.sub.4 residue, m being an integer from 1 to 7, wherein R.sub.4 is an amino, an amido, an amidino, a guanino, a guanidino, an imino or a pyridino residue.

15. The compound according to claim 12, wherein when R.sub.1 and R.sub.1′, or R.sub.2 and R.sub.2′, or R.sub.3 and R.sub.3′ are cationic residues, the residues being identical.

16. The compound according to claim 12, the compound being chosen from the compounds of the group consisting of: ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## wherein n is an integer from 1 to 4, or a compound of formula A1 to A10 having the formula A ##STR00077## wherein n varies from 1 to 6, and wherein TABLE-US-00012 R1 R2 R3 R′1 R′2 R′3 A1 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 A2 CH.sub.3 CH.sub.3 A3 CH.sub.3 CH.sub.3 A4 CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3 A5 CH.sub.3 CH.sub.3 A6 CH.sub.3 CH.sub.3 A7 CH.sub.3 CH.sub.3 CH.sub.3 A8 CH.sub.3 CH.sub.3 CH.sub.3 A9 CH.sub.3 CH.sub.3 CH.sub.3 A10

17. The compound according to claim 12, wherein the compound is chosen from the compounds of the group consisting of: ##STR00113## ##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118## ##STR00119## ##STR00120## ##STR00121##

18. A pharmaceutical composition comprising as active ingredient a compound according to claim 12, in association with a pharmaceutically acceptable carrier.

19. A method for treating infection caused by bacteria and fungi comprising the administration of an effective amount to an individual in a need therefore of a compound according to claim 12.

20. A method for the decontamination of a surface infected by bacteria and fungi comprising a step of applying onto the surface a compound according to claim 12.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0062] FIG. 1 represents analytical HPLC analysis of oligomer 1 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TPA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0063] FIG. 2 represents analytical HPLC analysis of oligomer 2 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0064] FIG. 3 represents analytical HPLC analysis of oligomer 3 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0065] FIG. 4 represents analytical HPLC analysis of oligomer 4 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0066] FIG. 5 represents analytical HPLC analysis of oligomer 5 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0067] FIG. 6 represents analytical HPLC analysis of oligomer 6 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0068] FIG. 7 represents analytical HPLC analysis of oligomer 7 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0069] FIG. 8 represents analytical HPLC analysis of oligomer 8 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0070] FIG. 9 represents analytical HPLC analysis of oligomer 9 (Chromolith Speed Rod RP-C.sub.18 185 Pm column 50×4.6 mm, 5 μm with a gradient from 100% (H.sub.2O/TFA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm)

[0071] FIG. 10 represents represent the description of the nomenclature and the torsion angles of the compounds,

[0072] FIG. 11 represents the circular dichroism spectra of oligomers (3), (4) and (5) in water at 20° C.

[0073] FIG. 12 represents the circular dichroism spectra of oligomers (6), (7), (8) and (9) in water at 20° C.

[0074] FIG. 13 represents the FT-IR spectra (1000-2000 cm.sup.−1) of oligomers (3), (4), (5), (6), (7), (8) and (9) in water at 20° C.

[0075] FIG. 14 represents A/ Nomenclature, characteristic H-bonding network of above mentioned compounds of formula A and schematic representation of the position of the side chains. B/ Designed antimicrobial γ-peptides 1-9. C/ Longitudinal and axial views of predicted conformations (C.sub.9-helix) for 4, 7, 9 based on previously reported structures of ATC oligomers.

[0076] FIG. 15 represents the syntheses of N-Face-γ-aminoacid related as above mentioned compounds of formula B and γ-peptides 1-9.

[0077] FIG. 16 A/ Superimposition of the NH/.sup.tCH region of the DIPSY (in blue) and NOESY (in red) spectra of 3 recorded in water pH 6.5. B/ Typical Inter-residue NOEs pattern along 3. C/ Superimposition of the 15 lowest energy NMR solution structures of 3 in water (lateral chains are omitted for clarity), D/ Representative structure of 3 (cationic lateral chains are in red). E/ FT-IR spectrum of 3 in water (pH 4.3) at 5 mM. F/ Far-UV CD spectrum of 3 in water (pH 4.3) at 25 μM between 200 and 300 nm.

[0078] FIG. 17 represents a graphic showing the results of a time-kill study of oligomer 9 on E. coli over 2 h incubation at 37° C. The γ-peptide 9 was evaluated at 0, 1.8 μM (MC), 7.2 μM (4×MIC) and 14.4 μM (8×MIC).

[0079] FIG. 18 represents electronic microscopy photos. A/, B/ and C/ SEM micrographs untreated E. coli on glass platelets. In isotonic medium the cells are long, intact and evenly shaped. D/, E/ and F/ After 60 min incubation with MIC of 9, the cells appear shorter and more compact and showed protruding vesicles on their corrugated surface. G/, H/ and I/ After 60 min incubation with 8×MIC of 9, the bacteria additionally showed small protruding bubbles on their surface leading to numerous spherical elements in the medium.

[0080] FIG. 19 represents SEM micrographs untreated E. coli after 60 min incubation with 8×MIC of 9. Left: blisters were visible on cell surface (see arrows), and right: numerous lysed cells were observed.

EXAMPLES

Example 1 Synthesis

[0081] I—General Procedures

[0082] All reagents and solvents were obtained from commercial sources and used without further purification. Analytical HPLC analyses were run on an Agilent. Technology 1220 Infinity LC equipped with a Chromolith Speed Rod RP-C18 185 Pm column (50×4.6 mm, 5 μm) with a gradient from 100% (H.sub.2O/TPA 0.1%) to 100% (CH.sub.3CN/TFA 0.1%) in 5 min; flow rate 4 mL/min; UV detection at 214 nm. Retention times are reported as follows: Rt (min). LC/MS analyses were recorded on a Quattro Micro™ ESI triple quadrupole mass spectrometer (Micromass, Manchester, UK) equipped with a Chromolith Speed Rod RP-C18 185 Pm column (50×4.6 mm, 5 μm) and an Alliance HPLC System (Waters, Milford, USA); gradient from 100% (H2O/HCO.sub.2H 0.1%) to 100% (CH.sub.3CN/HCO.sub.2H 0.1%) in 3 mill; flowrate 3 mL/min; UV detection at 214 nm. High-Resolution Mass Spectrometric analyses were performed with a time-of-flight (TOF) mass spectrometer fitted with an Electrospray Ionisation source (ESI) in positive ion mode.

[0083] II—Synthesis of N-Fmoc-γ-Aminoacid Related as Above Mentioned Compounds of Formula B—FIG. 15

[0084] 1. Synthesis of 10a, 10b, 10c and 10d

[0085] Intermediates 10a-d, 11a-d and N-Fmoc-γ-aminoacids 13a-d, 10b, 10c and 10d have been synthesized as previously reported. (L. Mathieu, C. Bonnet, N. Masurier, L. T. Maillard, J. Martinez, V. Lisowski, Eur. J. Org. Chem. 2015, 2015, 2262-2270).

[0086] 2. Synthesis of 15

##STR00058##

[0087] Step 1: To a solution of 5-(Boc-amino)pentanoic acid (1.0 equiv., 36.8 mmol, 8.0 q) in anhydrous THF at 0° C. and under argon atmosphere were sequentially added IBCF (1.2 equiv.) and triethylamine (1.2 equiv.). The white suspension was stirred for 10 min until complete formation of the mixed anhydride (HPLC monitoring). Then gaseous ammonia was bubbled for 30 min at r.t. to yield N-Boo-aminovaleramide I as a white powder. Yield quantitative (8.02 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.37 (s, 9H); 1.42-1.46 (m, 4H); 2.01 (t, J=7.2 Hz, 2H); 2.88 (m, 2H); 6.68 (s, 1H); 6.76 (t, 1H, J=5.4 Hz); 7.21 (s, .sup.1H).

[0088] Step 2: I (1.0 equiv., 36.8 mmol, 8.02 g.) was dissolved in dry DCM (180 mL). Then Lawesson's reagent was added in one portion (0.55 equiv., 20.3 mmol, 8.19 g.) and the white turbid mixture was heated at 32° C. overnight. After evaporation under reduced pressure, the yellow oil was dissolved in a mixture of DCM (200 mL) and aqueous saturated NaHCO.sub.3 solution (200 mL) which was stirred for 15 min. After transfer in a separating funnel, the organic layer was washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield crude product (orange oil) which was purified by chromatography on silica gel (Et2O/Petroleum ether: 5/5 to 9/1) to yield pure N-Boc-aminopentanethioamide 15 as white solid. Yield 50% (4.28 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 1.37 (s, 11H); 1.60 (quin, J=7.5 Hz, 2H); 2.44 (t, J=7.5 Hz, 2H); 2.89 (m, 2H); 6.78 (t, J=5.4 Hz, 1H); 9.11 (s, 1H); 9.31 (s, 1H). LC Rt=1.36 min. LC-MS: (ESI+): m/z 255.1 ([M+Na].sup.+) 90%, 233.1 ([M+H].sup.+) 25%, 133.1 ([M-Boc+H].sup.+) 100%.

[0089] 3. Synthesis of 16a

##STR00059##

[0090] A solution of 11a (1.0 equiv.) and 15 (2.0 equiv.) in EtOH was stirred 90 min at r.t. then 30 min at 40° C. After evaporation of the solvent under reduced pressure, the crude was purified by flash chromatography (Cyclohexane/EtOAc: 90/10 to 60/40) to yield II as a clear oil. Yield 56% (697 mg). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.44 (s, 9H); 1.47 (d, J=6.7 Hz, 3H); 1.59 (m, 2H); 1.63 (s, 3H); 1.65 (s, 3H); 1.82 (quin, J=7.6 Hz, 2H), 2.98 (t, J=7.6 Hz, 2H); 3.16 (brm, 2H); 4.22 (t, J=7.1 Hz, 1H); 4.35 (d, J=7.8 Hz, 2H); 4.66 (br, 1H); 5.15 (d, J=11.1 Hz, 1H); 5.26 (d, J=17.8 Hz, 1H); 5.67 (m, 1H); 6.02 (brm, 1H); 6.16 (dd, J=11.1, 17.8 Hz, 1H); 7.30 (m, 2H); 7.39 (t, J=7.4 Hz, 2H); 7.61 (t, J=7.7 Hz, 2H); 7.76 (d, J=7.4 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 22.1; 26.7 (2C); 27.9; 28.6 (3C); 29.5; 33.2; 40.2; 46.7; 47.4; 66.9; 79.4; 83.2; 113.6; 120.1 (2C); 122.8; 125.3 (2C); 127.1 (2C); 127.8 (2C); 141.4 (2C), 142.0; 144.1; 144.3; 155.7; 156.1; 160.4; 162.6; 174.5. LC Rt=2.62 min. LC-MS: (ESI+); m/z 656.1 ([M+Na].sup.+) 25%, 634.1 ([M+H].sup.+) 100%, 578.0 ([M-tBu-+2H].sup.+) 30%, 534.1 ([M-Boc+H].sup.+) 80%, 466.0 ([M-Boc-C.sub.5H.sub.9+H].sup.+) 55%, HRMS (ESI+) m/z calcd. for [C.sub.35H.sub.44N.sub.3O.sub.6S].sup.+: [M+H].sup.+ 634.2949, found 634.2951.

[0091] The O-dimethylallylester II (1.13 mmol) was dissolved in dry THF (5 mL). Tetrakis (triphenylphosphine)palladium(0) (3 mol %) was then added to the solution and the orange mixture was stirred for 5 min at r.t. Then PhSiH.sub.3 (1.2 equiv.) was added and the solution was stirred for 30 min (HPLC monitoring). The solvent was then evaporated under vacuum to yield 16a as a brown foam (630 mg).). LC Rt=2.12 min. LC-MS: (ESI+): m/z 588.2 ([M+Na].sup.+20%, 566.2 ([M+H].sup.+) 30%, 466.2 ([M-Boc+H].sup.+) 100%.

[0092] 4. Synthesis of 16b

##STR00060##

[0093] Step 1: 15 (1.1 equiv., 5.41 mmol) was dissolved in DME (35 mL) and then KHCO3 (8.0 equiv., 39.3 mmol) was added in one portion. The mixture was vigorously stirred for 30 min at r.t. 11 b was dissolved in 40 mL of DME and added to the mixture with a dropping funnel at 0° C. The reaction was stirred overnight at r.t. The crude was filtered to remove unsoluble KHCO.sub.3 and the clear filtrate was evaporated under reduced pressure. The resulting yellow oil was dissolved in EtOAc (100 mL) then washed with water (1×100 mL) and brine (1×50 mL), dried over MgSO4 and filtered. The solvent was evaporated to yield the corresponding thiazoline III as an orange foam. Yield quantitative (3.44 g). LC Rt=2.57 min. LC-MS: (ESI+): m/z 694.3 ([M+H].sup.+) 100%.

[0094] Step 2: The thiazoline III was dissolved in 50 mL of dry THF at −15° C. Dilsoproylethylamine (8.0 equiv., 39.3 mmol, 6.80 mL) was added and the mixture was stirred for 15 min. Then trifluoroacetic anhydride (4.0 equiv., 19.6 mmol, 2.74 mL) was added dropwise (4-5 min). After 30 min of stirring at −15° C., a second equiv. of trifluoroacetic anhydride was added to the orange-red solution in order to consume remaining thiazoline. After 10 min of stirring at −15° C. the mixture was diluted with DCM (100 mL) and washed with aqueous saturated NaHCO.sub.3 solution (2×100 mL), then with aqueous saturated KHSO.sub.4 solution (1×100 mL) and brine (1×50 mL). The organic layer was dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield 4.19 g of −15° C. IV as a red foam.

[0095] Step 3: KHCO.sub.3 (2.0 equiv., 9.82 mmol, 983 mg) was added to a solution of IV dissolved in dry MeOH (50 mL). The suspension was stirred overnight at r.t. then diluted with DCM (80 mL) and washed with aqueous saturated NaHCO.sub.3 solution (1×50 mL) and brine (2×70 mL). The organic layer was dried over MgSO.sub.4, filtered, concentrated under reduced pressure and filtered through a Celite pad to yield crude V as an orange foam which was used for the next step without further purification. Yield 93% (3.09 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.95 (d, J=6.4 Hz, 3H); 0.97 (d, J=6.4 Hz, 3H); 1.44 (s, 9H); 1.55-1.62 (m, 3H); 1.66 (s, 7H); 1.70-1.83 (m, 3H); 2.96 (t, J=7.6 Hz, 2H); 3.15 (brm, 2H); 4.21 (t, J=7.0 Hz, 1H); 4.30 (dd, J=7.5, 10.5 Hz, 1H); 4.39 (dd, J=7.5, 10.5 Hz 1H); 4.67 (brm, 1H); 5.14 (d, J=11.0 Hz, 1H); 5.26 (d, J=17.5 Hz, 1H); 5.70 (m, 1H); 5.84 (brm, 1H); 6.19 (dd, J=11.0, 17.5 Hz, 1H); 7.29 (m, 2H); 7.38 (t, J=7.3 Hz, 2H); 7.58 (d, J=7.1 Hz, 1H); 7.59 (d, J=5.3 Hz, 1H) 7.75 (d, J=7.3 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 22.3; 23.3; 25.1; 26.7; 26.8; 27.1; 28.5 (3C); 29.5; 33.2; 40.2; 45.2; 47.4; 49.0; 66.7; 79.4; 83.3; 113.5; 120.1 (2C); 123.4; 125.3 (2C); 127.1 (2C); 127.7 (2C); 141.4 (2C); 142.1; 144.1; 144.2; 155.9; 156.1; 160.5; 162.3; 174.4. LC Rt=2.92 min. LC-MS: m/z 698.2 ([M+Na].sup.+) 55%, 676.2 ([M+H].sup.+) 100%, 576.1 ([M-Boc+2H].sup.+) 75%, 508.1 ([M-C.sub.5H.sub.9+2H].sup.+), 50%. HRMS (ESI+) m/z calcd. for [C.sub.38H.sub.50N.sub.3O.sub.6S].sup.+: [M+H].sup.+ 676.3421, found 676.3420.

[0096] The O-dimethylallylester V (4.5 mmol) was dissolved in dry THF (25 mL). Tetrakis (triphenylphosphine)palladium(0) (3 mol %) was then added to the solution and the orange mixture was stirred for 5 min at r.t. Then PhSiH.sub.3 (1.2 equiv.) was added and the solution was stirred for 30 min (HPLC monitoring). The solvent was then evaporated under vacuum to yield 16b as a brown foam (1.25 g). LC Rt=2.34 min. LC-MS: (ESI+): m/z 630.2 ([M+Na].sup.+) 5%, 608.2 ([M+H].sup.+) 25%; 552.1 ([M-tBu+2H].sup.+) 15%; 506.1 ([M-Boc+2H].sup.+) 100%.

[0097] 5. Synthesis of 19

##STR00061##

[0098] Step 1: Isovaleryl chloride (1.0 equiv., 16.6 mmol, 2.0 mL) was diluted with 20 mL of dry THF under an argon atmosphere. Then ammoniac was bubbled into the solution for 30 min at 0° C. and the white turbid mixture was evaporated to yield quantitatively VI as a white powder (2.84 g). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.83 (d, J=6.4 Hz, 6H); 1.90-1.93 (m, 3H); 6.72 (s, 1H); 7.21 (s, 1H).

[0099] Step 2: VI (1.0 equiv., 16.6 mmol, 2.8 g) was dissolved in dimethoxyethane (DME, 120 mL) and Lawesson's reagent (0.55 equiv., 9.1 mmol, 3.7 g) was then added in one portion. The mixture was refluxed at 100° C. for 2 h (HPLC monitoring). Solvent was evaporated and the yellowish residue was dissolved in a mixture of EtOAc (100 mL) and aqueous saturated NaHCO.sub.3 solution (100 mL) which was stirred for 15 min. After transfer in a separating funnel, the organic layer was washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield crude product (yellow oil) which was purified by flash chromatography on silica gel (DCM 100% to DCM/MeOH: 94/6) to yield pure 18 as slight yellow crystals. Yield 43% (841 mg). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 0.98 (d, J=6.6 Hz, 6H); 2.23 (non, J=6.9 Hz, 1H); 2.50 (d, 2H, J=6.9 Hz); 6.90 (br, 1H); 7.76 (br, 1H). LC Rt=1.00 min. LC-MS: (ESI+): m/z 118.2 ([M+H].sup.+) 100%.

[0100] Step 3: A solution of 11a (1.0 equiv., 4.5 mmol, 2.25 g) and 18 (1.6 equiv.) in EtOH was stirred 4 h at 40° C. After evaporation of the solvent, the crude product was purified by flash chromatography (Cyclohexane 100% to Cyclohexane/EtOAc: 80/20) to yield pure VI as a clear oil. Yield 41% (952 mg). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 0.99 (s, 3H); 1.01 (s, 3H); 1.48 (d, J=6.7 Hz, 3H); 1.65 (s, 6H); 2.11 (non, J=6.7 Hz, 1H); 2.82 (d, J=7.1 Hz, 2H); 4.23 (t, J=7.00 Hz, 1H); 4.35 (m, 2H); 5.15 (d, J=10.9 Hz, 1H); 5.27 (d, J=17.3 Hz, 1H) 5.68 (m, 1H); 6.02 (d, J=8.7 Hz, 1H); 6.18 (dd, J=10.9, 17.3 Hz, 1H); 7.29 (d, J=7.6 Hz, 1H); 7.31 (d, J=7.3 Hz, 1H); 7.39 (d, J=7.6 Hz, 1H); 7.41 (d, J=7.3 Hz, 1H); 7.59 (d, J=4.9 Hz, 1H); 7.61 (d, J=7.3 Hz, 1H); 7.76 (d, J=7.6 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 22.3; 22.4 (2C); 26.7 (2C); 29.9; 42.6; 46.7; 47.4; 66.8; 83.1; 113.5; 120.1 (2C); 122.7; 125.3 (2C); 127.1 (2C); 127.7 (2C); 141.4 (2C); 142.0; 144.2; 144.3; 155.7; 160.5; 162.5; 174.0, LC Rt=2.85 min. LC-MS: (ESI+): m/z 541.1 ([M+Na].sup.+) 40%, 519.1 ([M+H].sup.+) 85%, 451.1 ([M-C.sub.5H.sub.9+2H].sup.+) 100%. HRMS (ESI+) m/z calcd, for [C.sub.30H.sub.35N.sub.2O.sub.4S].sup.+: [M+H].sup.+ 519.2318, found 519.2318.

[0101] The O-dimethylallylester VI (1.8 mmol) was dissolved in dry THF (10 mL). Tetrakis (triphenylphosphine)palladium(0) (3 mol %) was then added to the solution and the orange mixture was stirred for 5 min at r.t. Then PhSiH.sub.3 (1.2 equiv.) was added and the solution was stirred for 30 min (HPLC monitoring). The solvent was then evaporated under vacuum to yield 18 as a brown foam (1.25 g).). LC Rt=2.23 Mill. LC-MS: (ESI+): m/z 451.2 ([M+H].sup.+) 100%.

[0102] 6. Synthesis of 24

##STR00062## ##STR00063##

[0103] Step 1—synthesis of 21: To a solution of 4-(Boc-amino)butanoic acid 20 (1.0 equiv., 60 mmol, 12.2 g) in anhydrous THF at 0° C. and under argon atmosphere were sequentially added IBCF (1.2 equiv.) and triethylamine (1.2 equiv.). The white suspension was stirred for 10 min until complete formation of the mixed anhydride (HPLC monitoring). Then gaseous ammonia was bubbled for 30 min at r.t. to yield 4-(Boc-amino)-butylamide 22 as a white powder. Yield 92% (11.14 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.43 (s, 9H); 1.79 (quin, J=7.1 Hz, 2H); 2.26 (t, J=7.1 Hz, 1H); 2.36 (t, J=7.1 Hz, 1H); 3.17 (brm, H); 3H missing.

[0104] Step 2—synthesis of 22: 21 (1.0 equiv., 55.1 mmol, 11.1 g) was dissolved in dimethoxyethane (DME, 230 mL) and Lawesson's reagent (0.55 equiv., 30.3 mmol, 12.25 g) was then added in one portion. The mixture was refluxed at 100° C. for 2 h (HPLC monitoring). Solvent was evaporated and the yellowish residue was dissolved in a mixture of DCM (100 mL) and aqueous saturated NaHCO.sub.3 solution (100 mL) which was stirred for 15 min. After transfer in a separating funnel, the organic layer was washed with brine, dried over MgSO.sub.4, filtered and concentrated under reduced pressure to yield crude product (yellow oil) which was filtered on a Celite pad prior to purification by chromatography on silica gel (Cyclohexane/EtOAc: 60/40 to 30/70) to yield pure 22 as slight yellow crystals. Yield 38% (4.94 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.43 (s, 9H); 1.60 (quin, J=6.2 Hz, 2H); 2.72 (t, J=6.2 Hz, 2H); 3.21 (q, J=6.4 Hz, 2H); 4.79 (br, 1H); 7.64 (br, 1H); 8.71 (br, 1H). LC Rt=1.24 min. LC-MS: (ESI+): m/z 241.1 ([M+Na].sup.+) 5%, 219.1 ([M+H].sup.+) 20%, 163.1 ([M-tBu+2H].sup.+) 100%, 119.1 ([M-Boc+2H].sup.+) 45%.

[0105] Step 3—synthesis of VII: A solution of 6N HCl in 1,4-dioxane (50 mL) was added to 22 (1.0 equiv., 22.4 mmol, 4.89 g) and the mixture was stirred for 1 h at r.t. The reaction was monitored by HPLC. The solvent was evaporated in vacuo. Co-evaporation with MeOH yielded VII as a yellow oil. Quantitative yield (3.76 g). LC Rt=0.30 min (≥95%). LC-MS: (ESI+): m/z 118.9 ([M+H].sup.+) 100%.

[0106] Step 4 ® synthesis of IX: 1,4-dioxane (80 mL) was added to a solution of guanidine hydrochloride (1.0 equiv., 40 mmol, 3.82 g) and sodium hydroxide (4.0 equiv., 160 mmol, 6.42 g) dissolved in water (40 mL). The resulting mixture was cooled to 0° C. Di-tert-butyl-dicarbonate (2.2 equiv., 88 mmol, 19.2 g) was added in one portion and the reaction mixture was allowed to warm to room temperature overnight. Mixture was concentrated in vacuo to ⅓ of its original volume. The resulting suspension was diluted with water (80 mL) and extracted with EtOAc (3×90 mL). The combined organic layers were washed with 10% citric acid (150 mL), water (150 mL) and brine (150 mL) and dried with magnesium sulfate. After filtering and removal of the solvent under reduced pressure, the crude was purified by chromatography on silica gel (DCM/MeOH 99/1 to 96/4) to yield IX as a white powder. Yield 53% (5.46 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.41 (s, 18H); 8.48 (br, 1H); 10.35 (br, 2H). LC Rt=1.48 min (≥95%). LC-MS: (ESI+): m/z 260.1 ([M+H].sup.+) 70%, 204.3 ([M-tBu+2H].sup.+) 90%, 147.6 ([M−2tBu+3H].sup.+) 100%. LC Rt=2.26 min (≤5%; N,N′,N″-Tri(Boc)-guanidine). LC-MS: (ESI+); m/z 360.1 ([M+H].sup.+) 50%, 304.3 ([M-tBu+2H].sup.+) 75%, 248.1 ([M−2tBu+3H].sup.+) 75%, 192.0 ([M−3tBu+4H].sup.+) 100%, 148.1 ([M−2tBu-Boc+4H].sup.+) 60%.

[0107] Step 5—synthesis of X: A solution of IX (1.0 equiv., 21 mmol, 5.44 g) and triethylamine (1.08 equiv., 22.7 mmol, 3.1 mL) in anhydrous LLCM (105 mL) was cooled to −78° C. under an argon atmosphere. Triflic anhydride (1.05 equiv., 22.0 mmol, 3.71 mL) was added dropwise at a rate such that reaction temperature does not exceed −70° C. After the addition was completed, the reaction mixture was allowed to warm to room temperature within 4 hours. The solution was transferred to a separation funnel, washed with 2N MSC/land water and dried over magnesium sulfate. The organic layer was dried over MgSO4, filtered and concentrated under reduced to yield crude X as a slight yellow powder which was used for the next step without further purification. Yield 89% (7.3 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.46 (s, 18H); 11.05 (br, 2H). LC Rt=2.26 min (≥95%). LC-MS: (ESI+): m/z 392.0 ([M+H].sup.+) 5%, 336.1 90%, 280.1 95%, 236.2 100%.

[0108] Step 6—synthesis of 23: VII (1.1 equiv., 20.35 mmol, 3.15 g) was dissolved in a 1:1 mixture of DCM:MeOH (80 mL) and added in one time to a solution of X (1.0 equiv., 18.5 mmol, 7.24 g) and triethylamine (1.0 equiv., 18.5 mmol, 2.53 mL) dissolved in DCM (80 mL). After 80 min of stirring at r.t., reaction was stopped. Mixture was diluted with DCM (60 mL) and washed with water (100 mL), KHSO.sub.4. (100 mL), NaHCO.sub.3 (100 mL) and brine (100 mL). After filtering and removal of the solvent under reduced pressure, crude was purified by flash chromatography on silica gel (Cyclohexane/EtOAc 90/10 to 65/35) to yield pure 23 as a white powder. Yield 47% (3.14 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.44 (s, 9H); 1.49 (s, 9H); 1.96 (m, 2H); 2.81 (m, 2H); 3.44 (q, J=6.1 Hz, 2H); 7.72 (br, 1H); 8.58 (t, J=Hz, 1H); 10.41 (br, 1H); 11.36 (br, 1H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 28.1 (3C); 28.3 (3C); 29.4; 39.0; 43.4; 79.9; 83.9; 153.2; 157.3; 162.5; 209.4. LC Rt=1.65 min. LC-MS: (ESI+): m/z 361.0 ([M+H].sup.+) 100%, 305.1 ([M-tBu+2H].sup.+) 100%, 249.1 ([M−2tBu+3H].sup.+) 65%, 205.1 ([M−2tBu-Boc+4H].sup.+) 30%. HRMS (ESI+) m/z calcd. for [C.sub.15H.sub.29N.sub.4O.sub.4S].sup.+: [M+H].sup.+ 361.1910, found 361.1910.

[0109] Step 7 synthesis of XI: A solution of 11a (1.0 equiv., 4.91 mmol, 2.25 g) and 23 (1.5 equiv.) in EtOH was stirred 90 min at r.t. then 30 min at 40° C. After evaporation of the solvent, the crude was purified by flash chromatography (DCM 100% to DCM/EtOAc: 80/20) to yield XI as a neon yellow foam. Yield 27% (1.03 g). .sup.1H NMR (400 MHz, CDCl.sub.3) δ 1.48 (brm, 3H); 1.50 (s, 18H); 1.63 (m, 6H); 2.08 (t, J=7.2 Hz, 1H); 3.03 (t, J=7.6 Hz, 2H); 3.53 (brm, 2H); 4.22 (t, J=7.1 Hz, 1H); 4.33 (d, J=7.1 Hz, 2H); 5.15 (d, J=10.9 Hz, 1H); 5.24 (d, J=17.4 Hz, 1H); 5.26 (d, J=17.4 Hz, 1H) 5.69 (m, 1H); 6.02 (d, J=9.3 Hz, 1H); 6.16 (m, 1H, H.sub.2); 7.29 (td, J=7.4, 2.2 Hz, 2H); 7.38 (1, J=7.5 Hz, 2H); 7.59 (d, J=6.7 Hz, 1H); 7.61 (d, J=6.7 Hz, 1H); 7.75 (d, J=7.5 Hz, 2H). .sup.13C NMR (100 MHz, CDCl.sub.3) δ 22:2; 26.7 (2C); 28.2 (3C); 28:5 (3C); 29.0; 30.8; 39.8; 46.7; 47.4; 66.9; 79.5; 83.2; 83.4; 113.6; 120.1 (2C); 122.9; 125.3 (2C), 127.1 (2C), 127.7 (2C); 141.4 (2C); 142.0; 144.1; 144.3 (C.sub.14); 153.4; 155.7; 156.4; 160.3; 162.8; 163.8; 173.4. LC Rt=2.58 min. LC-MS: (ESI+): m/z 762.4 ([M+H].sup.+) 100%, 662.3 ([M-Boc+2H].sup.+) 75%, 562.2 ([M−2Boc+3H].sup.+) 20%. HRMS (ESI+) m/z calcd. for [C.sub.40H.sub.52N.sub.5O.sub.8S].sup.+: [M+H].sup.+762.3543, found 762.3537.

[0110] Step 8 Synthesis of 24:

[0111] The O-dimethylallylester XI (1.3 mmol) was dissolved in dry THF (5 mL). Tetrakis (triphenylphosphine)palladium(0) (3 mol %) was then added to the solution and the orange mixture was stirred tor 5 min at r.t. Then PhSiH.sub.3 (1.2 equiv.) was added and the solution was stirred for 30 min (HPLC monitoring). The solvent was then evaporated under vacuum to yield 24 as a brown foam (1.25 g). LC Rt=2.18 min. LC-MS: (ESI+): m/z 694.2 ([M+H].sup.+) 100%, 594.2 ([M-Boc+2H].sup.+) 40%, 494.2 ([M−2Boc+3H].sup.+) 5%.

[0112] III. Synthesis of Sequences 1, 2, 3, 4, 6, 7, 8, 9 Related as Above Mentioned Compounds of Formula A

[0113] 1. General Procedure of Solid Phase Synthesis

[0114] Solid-phase synthesis was performed on a ChemMatrix® Rink Amide resin loaded at 0.49 mmol/g using Fmoc/t-Bu chemistry. Resin was swollen in N-methylpyrrolidone (NMP) for 5-10 minutes and filtered. N-Fmoc-γ-aminoacid (1.5 equiv.), DIC (1.5 equiv.), Oxyma Pure (1.5 equiv.), and NMP were added in this order for each peptide coupling (overnight at r.t.). Resin was washed using the following procedure; 3×DMF, 3×DCM, 3×MeOH, 1×DMF, 1×MeOH, 1×DCM. Each coupling was followed by a capping step with a Ac.sub.2O/DCM 1/1 vv solution (1×5 min at r.t.) and washed. Deprotection at the N-terminus was performed using a 20% piperidine/DMF solution (3×10 min at r.t.) and the resin was then washed before the next coupling. Deprotection and coupling steps were monitored by Kaiser test. After completion of the oligomerization process, the foldamer was N-deprotected (3×10 min at r.t.), capped (2×5 min at r.t.) and cleaved from the resin with a TFA/TIS/H.sub.2O 95/2.5/2.5 vvv solution (2×90 min at r.t.). The resin was washed (1×DCM and 1×cleavage cocktail) and filtered to retrieve the filtrate which was evaporated under reduced pressure. Crude foldamer was precipitated with cold diethylether, centrifugated 10 min at 5° C. and lyophilized. Purification by preparative RP-HPLC was performed on a Waters system controller equipped with a C.sub.18 Waters Delta-Pack column (100×40 mm, 100 Å) flow 50 mL/min; UV detection at 214 nm using a Waters 486 Tunable Absorbance Detector and a linear gradient of A=H.sub.2O (0.1% TFA) and B═CH.sub.3CN (0.1% TFA).

[0115] 2. Oligomer 1

[0116] 1 was synthesized according to solid phase general procedures starting from 1 mmol of resin. Crude (≈0.25-0.3 mmol) was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 16% (40 mg). Gradient (% of eluent B): 0.fwdarw.10 (2 min), 10.fwdarw.15 (3 min), 15.fwdarw.40 (25 min), LC Rt=1.91 min. LC-MS: (ESI+): m/z 339.6 ([M+2H].sup.2+) 100%.

[0117] Results of the RP-HPLC are shown in FIG. 1.

[0118] 3. Oligomer 2

[0119] 2 was synthesized according to solid phase general procedures described in Section VI.1, starting from 0.7 mmol of the corresponding resin-linked fully protected haler. Crude (≈0.20-0.30 mmol) was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 12% (45 mg). Gradient (% of eluent B): 0.fwdarw.15 (2 min), 15.fwdarw.20 (3 min), 20.fwdarw.40 (20 min), LC Rt=2.16 min. LC-MS: (ESI+): m/z 649.5 ([M+2].sup.2+) 10%, 433.1 ([M+3H].sup.3+) 60%, 325.3 ([M+4H].sup.4+) 100%.

[0120] Results of the RP-HPLC are shown in FIG. 2,

[0121] 4. Oligomer 3

[0122] 3 was synthesized according to solid phase general procedures described in Section VI.1. starting from 0.4 mmol of the corresponding resin-linked fully protected hexamer. Crude (≈0.20-0.25 mmol) was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 16% (61 mg). Gradient (% of eluent B): 0.fwdarw.15 (2 min), 15.fwdarw.23 (5 min), 23.fwdarw.40 (17 min). LC Rt=2.26 min. LC-MS: (ESI+): m/z 958.5 ([M+2H].sup.2+) 10%, 639.4 ([M+3H].sup.3+) 35%, 325.3 ([M+4H].sup.4+) 75%, 384.0 ([M+5H].sup.5+) 100%, 320.2 ([M+6H].sup.6+) 15%.

[0123] Results of the RP-HPLC are shown in FIG. 3.

[0124] The following table 1 represents the .sup.1HNMR chemical shifts for 3 in H2O/D2O (9:1) pH 6.5 at 283 K. The nomenclature of 3 is described FIG. 10. 3 has the following formula:

##STR00064##

TABLE-US-00002 TABLE 1 Residue HN .sup.γCH .sup.δCH Others Ac — — — CH.sub.3 2.07 Res. 1 8.78 5.08 1.89 .sup.εCH.sub.2 0.89 .sup.ζCH.sub.2 1.44 .sup.ηCH.sub.2 2.76 .sup.τ1CH.sub.3 2.69 Res. 2 10.13 5.46 1.56 .sup.τ1CH.sub.2 3.08 .sup.τ2CH.sub.2 1.89 .sup.τ3CH.sub.2 1.77 .sup.τ4CH 2.97 Res. 3 9.91 5.52 1.57 .sup.τ1CH.sub.3 2.73 Res. 4 9.70 5.37 2.05 .sup.εCH.sub.2 1.05 .sup.ζCH.sub.2 1.53 .sup.ηCH.sub.2 2.84 .sup.τ1CH.sub.3 2.70 Res. 5 9.88 5.47 1.57 .sup.τ1CH.sub.2 nd .sup.τ2CH.sub.2 nd .sup.τ3CH.sub.2 nd .sup.τ4CH nd Res. 6 9.77 5.52 1.57 .sup.τ1CH.sub.3 2.72 Res. 7 9.58 5.37 2.03 .sup.εCH.sub.2 1.08 .sup.ζCH.sub.2 1.53 .sup.ηCH.sub.2 2.84 .sup.τ1CH.sub.3 2.67 Res. 8 9.80 5.54 1.59 .sup.τ1CH.sub.2 nd .sup.τ2CH.sub.2 nd .sup.τ3CH.sub.2 nd .sup.τ4CH nd Res. 9 9.72 5.61 1.57 .sup.τ1CH.sub.3 2.64 NH.sub.2 8.48- — — — 7.64

[0125] 5. Oligomer 4

[0126] 4 was synthesized according to solid phase general procedures described in Section VI.1. starting from 0.4 mmol of of the corresponding resin-linked fully protected nonamer. Crude (≈0.20-0.25 mmol) was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 19% (95 mg). Gradient (% of eluent B): 0.fwdarw.20 (3 min), 20.fwdarw.25 (3 min), 25.fwdarw.45 (20 min). LC Rt=2.31 min. LC-MS: (ESI+): m/z 1268.3 ([M+2H].sup.2+) 5%, 845.8 ([M+3H].sup.3+) 35%, 634.3 ([M+4H].sup.4+) 55%, 507.7 ([M+5H].sup.5+) 95%, 423.3 ([M+6H].sup.6+) 100%, 363.1 ([M+7H].sup.7+) 55%.

[0127] Results of the RP-HPLC are shown in FIG. 4.

[0128] The following table 2 represents the .sup.1HNMR chemical shifts for 4 in H.sub.2O/D.sub.2O (9:1) pH 6.5 at 283 K. The nomenclature of 4 is described FIG. 10. 4 has the following formula:

##STR00065##

TABLE-US-00003 TABLE 2 Residue HN .sup.γCH .sup.δCH Others Ac — — — CH.sub.3 2.07 Res. 1 8.76 5.09 1.89 .sup.εCH.sub.2 0.92 .sup.ζCH.sub.2 1.45 .sup.ηCH.sub.2 2.78 Res. 2 10.13 5.49 1.56 .sup.τ1CH.sub.2 nd .sup.τ2CH.sub.2 nd .sup.τ3CH.sub.2 nd .sup.τ4CH nd Res. 3 9.91 5.54 1.57 .sup.τ1CH.sub.3 2.73 Res. 4 9.65 5.38 2.05 .sup.εCH.sub.2 1.07 .sup.ζCH.sub.2 1.56 .sup.ηCH.sub.2 2.85 Res. 5 9.89 5.49 1.56 .sup.τ1CH.sub.2 nd .sup.τ2CH.sub.2 nd .sup.τ3CH.sub.2 nd .sup.τ4CH nd Res. 6 9.77 5.54 1.57 .sup.τ1CH.sub.3 2.71 Res. 7 9.53 5.40 2.05 .sup.εCH.sub.2 1.07 .sup.□CH.sub.2 1.56 .sup.□CH.sub.2 2.85 Res. 8 9.86 5.51 1.56 .sup.τ1CH.sub.2 3.03-3.05 .sup.τ2CH.sub.2 1.89 .sup.τ3CH.sub.2 1.80 .sup.τ4CH 2.97 Res. 9 9.62 5.53 1.56 .sup.τ1CH.sub.3 2.65 Res. 10 9.53 5.40 2.05 .sup.εCH.sub.2 1.07 .sup.ζCH.sub.2 1.56 .sup.ηCH.sub.2 2.85 Res. 11 9.82 5.53 1.56 .sup.τ1CH.sub.2 nd .sup.τ2CH.sub.2 nd .sup.τ3CH.sub.2 nd .sup.τ4CH nd Res. 12 9.72 5.61 1.57 .sup.γCH.sub.3 2.64 NH.sub.2 8.45- — — — 7.62

[0129] 7. Oligomer 6

[0130] 6 was synthesized according to solid phase general procedures described in Section VI.1. starting from 0.4 mmol of ChemMatrix Rink Amide resin. The crude was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 6% (34 mg). Gradient (% of eluent B): 0.fwdarw.40 (2 min), 40.fwdarw.45 (3 min), 45.fwdarw.465 (20 min). LC Rt=3.18 min. LC-MS: (ESI+); m/z 1084.6 ([M+2H].sup.2+) 20%; 723.5 ([M+3H].sup.3+) 70%, 542.9 ([M+4H].sup.4+) 80%, 434.6 ([M+5H].sup.5+) 100%, 362.2 ([M+6H].sup.6+) 15%.

[0131] Results of the RP-HPLC are shown in FIG. 6.

[0132] The following table 3 represents the .sup.1HNMR chemical shifts for 6 in CD3OH at 278 K. The nomenclature of 6 is described FIG. 10. 6 has the following formula:

##STR00066##

TABLE-US-00004 TABLE 3 Residue HN .sup.γCH .sup.δCH Others Ac — — — CH.sub.3 2.00 Res. 1 8.81 5.25 1.90 .sup.εCH.sub.2 1.02-1.13 .sup.ζCH.sub.2 1.52 .sup.ηCH.sub.2 2.77 .sup.τ1CH.sub.3 2.68 Res. 2 10.23 5.36 2.01- .sup.εCH.sub.2 1.05 .sup.ζ1−2CH.sub.2 0.56-0.81 1.76 .sup.τ1CH.sub.2 3.06 .sup.τ2CH.sub.2 1.89 .sup.τ3CH.sub.2 1.76 .sup.τ4CH 2.97 Res. 3 10.56 5.82 1.64 .sup.τ1CH.sub.3 2.84 .sup.τ2CH.sub.2 2.10 .sup.τ3CH.sub.2 0.99 Res. 4 10.16 5.49 2.09 .sup.εCH.sub.2 1.21-1.33 .sup.ζCH.sub.2 1.60 .sup.ηCH.sub.2 2.84 .sup.τ1CH.sub.3 2.71 Res. 5 9.92 5.39 1.83- .sup.εCH.sub.2 1.18 .sup.ζ1−2CH.sub.2 0.63-0.82 1.98 .sup.τ1CH.sub.2 3.06 .sup.τ2CH.sub.2 1.89 .sup.τ3CH.sub.2 1.76 .sup.τ4CH 2.97 Res. 6 10.59 5.86 1.65 .sup.τ1CH.sub.3 2.84 .sup.τ2CH.sub.2 2.10 .sup.τ3CH.sub.2 0.99 Res. 7 10.11 5.49 2.08 .sup.εCH.sub.2 1.23-1.33 .sup.γCH.sub.2 1.59 .sup.γCH.sub.2 2.82 .sup.γCH.sub.3 2.72 Res. 8 10.12 5.40 1.87- .sup.γCH.sub.2 1.20 .sup.γCH.sub.2 0.63-0.83 1.98 .sup.γCH.sub.2 3.06 .sup.γCH.sub.2 1.89 .sup.γCH.sub.2 1.76 .sup.γCH 2.97 Res. 9 10.45 5.76 1.68 .sup.γCH.sub.3 2.84 .sup.γCH.sub.2 2.10 .sup.γCH.sub.2 0.99 NH.sub.2 8.74- — — — 7.70

[0133] 8. Oligomer 7

[0134] 7 was synthesized according to solid phase general procedures described in Section VI.1. Crude was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 5% (61 mg). Gradient (% of eluent B): 0.fwdarw.50 (5 min), 50.fwdarw.54 (2 min), 54.fwdarw.70 (16 min). LC Rt=3.49 min. LC-MS: (ESI+): m/z 1436.5 ([M+2H].sup.2+) 10%; 958.0 ([M+3H].sup.3+) 40%, 718.8 ([M+4H].sup.4+) 50%, 575.5 ([M+5H].sup.5+) 95%, 479.5 ([M+6H].sup.6+) 100%, 411.1 ([M+7H].sup.7+) 40%, 359.7 ([M+8H].sup.8+) 5%.

[0135] Results of the RP-HPLC are shown in FIG. 7.

[0136] The following table 4 represents the .sup.1HNMR chemical shifts for 7 in CD.sub.3OH at 278 K. The nomenclature of 7 is described FIG. 10. 7 has the following formula

##STR00067##

TABLE-US-00005 TABLE 4 Residue HN .sup.γCH .sup.δCH Others Ac — — — CH.sub.3 1.99 Res 1 8.82 5.25 1.91 .sup.εCH.sub.2 1.02-1.13 .sup.ζCH.sub.2 1.52 .sup.ηCH.sub.2 2.76 .sup.τ1CH.sub.3 nd Res. 2 10.25 5.35 2.03- .sup.γCH.sub.2 1.06 .sup.ζ1−2CH.sub.2 0.56-0.81 1.77 .sup.τ1CH.sub.2 3.07 .sup.τ2CH.sub.2 1.89 .sup.τ3CH.sub.2 1.76 .sup.τ4CH 2.97 Res. 3 10.57 5.82 1.63 .sup.τ1CH.sub.3 2.84 .sup.τ2CH.sub.2 2.10 .sup.γCH.sub.2 0.99 Res. 4 10.19 5.47 2.08 .sup.γCH.sub.2 1.21-1.33 .sup.γCH.sub.2 1.61 .sup.γCH.sub.2 2.83 .sup.γCH.sub.3 nd Res. 5 10.17 5.38 1.87- .sup.γCH.sub.2 1.18 .sup.γCH.sub.2 0.64-0.84 .sup.γCH.sub.2 1.98 3.06 .sup.γCH.sub.2 1.89 .sup.γCH.sub.2 1.76 .sup.γCH 2.97 Res. 6 10.63 5.85 1.65 .sup.γCH.sub.3 2.84 .sup.γCH.sub.2 2.10 .sup.γCH.sub.2 0.99 Res. 7 10.13 5.48 2.09 .sup.γCH.sub.2 1.21-1.33 .sup.γCH.sub.2 1.62 .sup.γCH.sub.2 2.84 .sup.γCH.sub.3 nd Res. 8 9.95 5.39 1.87- .sup.γCH.sub.2 1.21 .sup.γCH.sub.2 0.64-0.84 .sup.γCH.sub.2 1.98 3.07 .sup.γCH.sub.2 1.89 .sup.γCH.sub.2 1.76 .sup.γCH 2.97 Res. 9 10.59 5.83 1.65 .sup.γCH.sub.3 2.84 .sup.γCH.sub.2 2.10 .sup.γCH.sub.2 0.99 Res. 10 10.22 5.48 2.08 .sup.γCH.sub.2 1.22-1.33 .sup.γCH.sub.2 1.60 .sup.γCH.sub.2 2.83 .sup.γCH.sub.3 nd Res. 11 10.14 5.39 1.83- .sup.γCH.sub.2 1.18 .sup.γCH.sub.2 0.64-0.83 .sup.γCH.sub.2 1.97 3.07 .sup.γCH.sub.2 1.89 .sup.γCH.sub.2 1.76 .sup.γCH 2.97 Res. 12 10.45 5.77 1.67 .sup.γCH.sub.3 2.84 .sup.γCH.sub.2 2.10 .sup.γCH.sub.2 0.99 NH.sub.2 8.75- — — — 7.70

[0137] 9. Oligomer 8

[0138] 8 was synthesized according to solid phase general procedures described in Section VI.1. starting from 0.4 mmol of ChemMatrix Rink Amide resin. Crude was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 5% (30 mg). Gradient (% of eluent B): 0.fwdarw.20 (3 min), 20.fwdarw.25 (2 min), 25.fwdarw.45 (25 min). LC Rt=2.28 min. LC-MS: (ESI+): m/z 1043.0 ([M+2H].sup.2+) 10%; 695.5 ([M+3H].sup.3+) 40%, 521.8 ([M+4H].sup.4+) 60%, 417.6 ([M+5H].sup.5+) 100%, 348.2 ([M+6H].sup.6+) 40%.

[0139] Results of the RP-HPLC are shown in FIG. 8.

[0140] The following table 5 represents the .sup.1HNMR chemical shifts for 8 in CD.sub.3OH at 278 K. The nomenclature of 8 is described FIG. 10. 8 has the following formula:

##STR00068##

TABLE-US-00006 TABLE 5 Residue HN .sup.γCH .sup.δCH Others Ac — — — CH.sub.3 1.99 Res. 1 8.86 5.29 1.91 .sup.εCH.sub.2 1.36-1.19 .sup.ζCH.sub.2 3.06 .sup.τ1CH.sub.3 nd Res. 2 10.25 5.69 1.57 .sup.τ1CH.sub.2 3.07 .sup.γCH.sub.2 2.07 .sup.γCH.sub.2 3.28 Res. 3 10.29 5.69 1.58 .sup.γCH.sub.3 nd Res. 4 10.22 5.53 2.08 .sup.γCH.sub.2 1.54-1.38 .sup.γCH.sub.2 3.13 .sup.γCH.sub.3 nd Res. 5 9.99 5.71 1.59 .sup.γCH.sub.2 3.07 .sup.γCH.sub.2 2.07 .sup.γCH.sub.2 3.28 Res. 6 10.32 5.72 1.61 .sup.γCH.sub.3 2.70 Res. 7 10.15 5.52 2.07 .sup.γCH.sub.2 1.54-1.43 .sup.γCH.sub.2 3.14 .sup.γCH.sub.3 nd Res. 8 9.77 5.75 1.60 .sup.γCH.sub.2 3.07 .sup.γCH.sub.2 2.07 .sup.γCH.sub.2 3.28 Res. 9 10.19 5.65 1.64 .sup.γCH.sub.3 nd NH.sub.2 8.62- — — — 7.67

[0141] 10. Oligomer 9

[0142] 9 was synthesized according to solid phase general procedures described in Section VI.1. Crude was purified by preparative RP-HPLC to yield the pure peptide as a pulverulent white powder. Yield 5% (37 mg). Gradient (% of eluent B): 0.fwdarw.25 (2 min), 25.fwdarw.28 (2 min), 28.fwdarw.48 (25 min). LC Rt=2.35 min. LC-MS: (ESI+): m/z 920.5 ([M+3H].sup.3+) 25%, 690.6 ([M+4H].sup.4+) 70%, 552.5 ([M+5H].sup.5+) 85%, 460.7 ([M+6H].sup.6+) 100%, 395.0 ([M+7H].sup.7+) 70%, 345.8 ([M+8H].sup.8+) 15%.

[0143] Results of the RP-HPLC are shown in FIG. 9.

[0144] The following table 6 represents the .sup.1HNMR chemical shifts for 9 in CD.sub.3OH at 278 K. The nomenclature of 9 is described FIG. 10. 9 has the following formula:

##STR00069##

TABLE-US-00007 TABLE 6 Residue HN .sup.γCH .sup.δCH Others Ac — — — CH.sub.3 1.99 Res. 1 8.87 5.29 1.92 .sup.εCH.sub.2 1.36-1.19 .sup.ζCH.sub.2 3.07 .sup.τ1CH.sub.3 nd Res. 2 10.25 5.52 1.57 .sup.τ1CH.sub.2 3.10 .sup.τ2CH.sub.2 2.07 .sup.τ3CH.sub.2 3.29 Res. 3 10.05 5.72 1.60 .sup.τ1CH.sub.3 nd Res. 4 10.26 5.69 2.08 .sup.εCH.sub.2 1.58-1.38 .sup.ζCH.sub.2 3.14 .sup.τ1CH.sub.3 nd Res. 5 10.30 5.68 1.59 .sup.τ1CH.sub.2 3.10 .sup.τ2CH.sub.2 2.07 .sup.τ3CH.sub.2 3.29 Res. 6 10.37 5.71 1.62 .sup.τ1CH.sub.3 nd Res. 7 10.25 5.52 2.09 .sup.εCH.sub.2 1.56-1.39 .sup.ζCH.sub.2 3.14 .sup.τ1CH.sub.3 nd Res. 8 10.00 5.71 1.61 .sup.τ1CH.sub.2 3.10 .sup.τ2CH.sub.2 2.07 .sup.τ3CH.sub.2 3.29 Res. 9 10.33 5.73 1.61 .sup.τ1CH.sub.3 nd Res. 10 10.15 5.53 2.07 .sup.εCH.sub.2 1.55-1.43 .sup.ζCH.sub.2 3.14 .sup.τ1CH.sub.3 nd Res. 11 9.78 5.75 1.60 .sup.τ1CH.sub.2 3.10 .sup.τ2CH.sub.2 2.07 .sup.τ3CH.sub.2 3.29 Res. 12 10.19 5.65 1.64 .sup.τ1CH.sub.3 nd NH.sub.2 8.62- — — — 7.67

[0145] IV. Synthesis of Scrambled Sequence 5 (Helical but not Amphipathic/Amphiphilic)

[0146] 5 was synthesized according to solid phase general procedures described in Section VI.1. starting from 0.15 mmol of ChemMatrix Rink Amide resin. Crude was purified by preparative RP-HPLC to yield 5 as a pulverulent white powder. Yield 18% (92 mg). Gradient (% of eluent B): 0.fwdarw.15 (2 min), 15.fwdarw.20 (3 min), 20.fwdarw.40 (25 min). LC Rt=2.14 min. LC-MS: (ESI+): m/z 845.4 ([M+3H].sup.3+) 30%, 634.4 ([M+4H].sup.4+) 55%, 507.9 ([M+5H].sup.5+) 80%, 423.3 ([M+6H].sup.6+) 100%, 362.9 ([M+7H].sup.7+) 50%.

[0147] Results of the RP-HPLC are shown in FIG. 5.

Example 2 Structural Analysis of the Polycationic and Facially Amphiphilic Helical Molecular Pseudo-Peptide Architectures

[0148] Previous structural investigations have demonstrated that ATC oligomers appeared to be closed to a C.sub.3-symmetry helix with three residues to achieve a complete rotation. The architecture is stabilized by a highly stable hydrogen-bonding pattern between residues i and i+2 and exhibits six substituents per turn distributed around a 60° angle along the axis. Side chain positioning defines three distinct faces over the γ-peptide (FIG. 14 A/). Substituents R.sub.1, R.sub.1′ as defined above share the first face. Substituents R.sub.2, R.sub.2′ as defined above share the second face. Substituents R.sub.3, R.sub.3′ as defined above share the third face. On the basis of this topology, sequences 1-4 and 6-9 (FIG. 14B/) were designed to display one polycationic face and two hydrophobic faces (FIG. 14 C/). Oligomer 5 was designed as a scrambled sequence that does not display segregation of the cationic charges along one face of the helical architecture.

[0149] Circular dichroism (CD), NMR and FT-IR structural markers of the helical conformation of triazole-based γ-peptides named ATC-peptides have been previously reported (C. Bonnet, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664-8669; L. Mathieu, B Legrand, C. Deng, L. Vezenkov, E. Wenger, C. Didierjean, M. Amblard M. C. Averlant-Petit, N. Masurier, V. Lisowski, J. Martinez, L. T. Maillard, Angew. Chem., Int. Ed. Engl. 2013, 52, 6006-6010):

[0150] Procedures for NMR experiments: 3, 4 (2-4 mM) were dissolved in H.sub.2O/D.sub.2O (pH 6.5) while 6, 7, 8 and 9 (2-4 mM) were dissolved in CD.sub.3OH. All spectra were recorded on a Bruker Avarice 600 AVANCE III spectrometer equipped with a 5 mm triple-resonance cryoprobe (1H, 13C, 15N). Homonuclear 2-D spectra DQF-COSY, TOCSY (DIPSI2) and ROESY were typically recorded in the phase-sensitive mode using the States-TPPI method as data matrices of 256-512 real (t1)×2048 (t2) complex data points; 8-48 scans per t1 increment with 1.0 s recovery delay and spectral width of 6009 Hz in both dimensions were used. The mixing times were 60 ins for TOCSY and 350-450 ms for the ROESY experiments. In addition, 2D heteronuclear spectra 15N, 130-HSQC and 13C-HSQC-TOCSY were acquired to fully assign the oligormers (8-32 scans, 256-512 real (t1)×2048 (t2) complex data points). Spectra were processed with Topspin (Bruker Biospin) and visualized with Topspin or NMRview on a Linux station. The matrices were zero-filled to 1024 (t1)×2048 (t2) points after apodization by shifted sine-square multiplication and linear prediction in the F1 domain. Chemical shifts were referenced to the solvent.

[0151] Procedures for molecular modeling studies: .sup.1H chemical shifts were assigned according to classical procedures. NOE cross-peaks were integrated and assigned within the NMRView software (B. A. Johnson, P. A. Blevins, J. Biomol. NMR 1994, 4, 603 1994, 4). The volume of a ROE between methylene pair protons was used as a reference of 1.8 Å. The lower bound for all restraints was fixed at 1.8 Å and upper bounds at 2.7, 3.3 and 5.0 Å, for strong, medium and weak correlations, respectively (K. Wüthrich, NMR of Proteins and Nucleic acids; Wiley-Interscience: New York, 1986) Pseudo-atoms corrections of the upper bounds were applied for unresolved aromatic, methylene and methyl protons signals. Structure calculations were performed with AMBER 16 (D. A. Case, T. A. Darden, T. E. Cheatham III, C. L. Simmerling, J. Wang, R. E. Duke, R. Luo. M. Crowley; R. C. Walker, W. Zhang, K, M. Merz, B. Wang, S. Hayik, A. Roitberg, G. Seabra, 1. Kolossvry, K F. Wong, F. Paesani, J. Vanicek, X, Wu S. R. Brozell, T. Steinbrecher, H. Gohlke, L. Yang, C. Tan, J. Mongan, V. Hornak G. Cui, D. H. Mathews, M. G. Seetih, C. Sagui, V. Sabin and P. A. Kollman, Amber 10, University of California, San Francisco, 2008) in two stages: cooking and simulated annealing with the generalized Born (GB) implicit solvent model. The cooking stage was performed at 1000 K to generate 100 initial random structures, SA calculations were carried during 20 ps (20000 steps, 1 fs long) as described elsewhere. First, the temperature was risen quickly and was maintained at 600 K for the first 5000 steps, then the system was cooled gradually from 600 K to 100 K from step 5001 to 18000 and finally the temperature was brought to 0 K during the 2000 remaining steps. For the 3000 first steps, the force constant of the distance restraints was increased gradually from 2.0 kcal.Math.mol-1.Å to 20 kcal.Math.mol-1.Å. For the rest of the simulation (step 3001 to 20000), the force constant is kept at 20 kcal.Math.mol-1.Å. The calculations were launched in vacuum. The 10 lowest energy structures with no violations >0.3 Å were considered as representative of the peptide structure. The representation and quantitative analysis were carried out using MOLMOL (R. Koradi, M. Billeter, K Wuthrich, J. Mol. Graph. 1996, 14, 51) and Chimera (Delano Scientific Pettersen E F, Goddard T D, Huang C C, Couch G S, Greenblatt D M, Meng E C, Ferrin T E. J. Comput. Chem. 2004, 25, 1605-1612).

[0152] Procedure for Circular Dichroism (CD) Experiments:

[0153] CD were carried out using a Jasco J815 spectropolarimeter. The spectra were obtained in water, pH 6.0 using a 1 mm path length CD cuvette, at 20° C., over a wavelength range of 190-300 nm. Continuous scanning mode was used, with a response of 1.0 s with 0.2 nm steps and a bandwidth of 2 nm. The signal to noise ratio was improved by acquiring each spectrum over an average of two scans. Baseline was corrected by subtracting the background from the sample spectrum. The samples were dissolved in water at 25 μM.

[0154] FIGS. 11 and 12 represents CD spectra of oligomers (3), (4), (5), and (6), (7), (8) and (9) in water at 20° C., respectively.

[0155] Procedure for FT-IR Experiments:

[0156] Middle-infrared experiments (1000-2000 cm.sup.−1) were recorded in the ATR mode equipped with a diamond crystal. The measurements were carried out on a Perkin-Elmer Spectrum one FT-IR spectrometer equipped with a deuterated (L)-alanine triglycine sulphate (FR-DTGS) pyroelectric detector, a Globar source, and potassium bromide (KBr) beam splitter. The spectral resolution was 4 cm-1, and 64 scans were co-added for each spectrum. The compounds were dissolved at 5 mM concentration in water and 10 μl solutions were deposited on the ATR crystal. The FT-IR spectra were smoothed. Baseline substraction and deconvolution were performed using IGOR Pro 6.0 software (WaveMetrics). The deconvolution using a sum of Gaussian functions (in dash lines) and the overall fit (in red) are also shown.

[0157] Evidences of the Facially Amphiphilic Morphology of the Oligomer 3:

[0158] The far-UV CD spectrum of 3 was recorded in water (pH 6.0) at 25 μM between 200 and 300 nm. With two minima at 208 and 220 nm and a strong maximum at 265 nm, the CD signature is consistent with a C.sub.9-helical folding. (C. Bonnet, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2076, 14, 8664-8669) In addition, the molar ellipticity value per residue (73600 deg.Math.cm.sup.−2 dmol.sup.−1 for 3 at 265 nm) was similar to the previously value (74000 deg.Math.cm.sup.−2.Math.dmol.sup.−1) reported for helical ATC-oligomers in water.

[0159] NMR analyses of 3 were conducted in H.sub.2O/D.sub.2O (9:1), pH 6.5. As previously observed on ATCs-containing oligomers, (L. Mathieu, B. Legrand, C. Deng, L. Vezenkov, E. Wenger, C. Didierjean, M. Amblard, M, C. Averlant-Petit, N. Masurier, V. Lisowski, J. Martinez, L. T. Maillard, Angew. Chem., Int. Ed. Engl. 2013, 52, 6006-6010; B. Legrand L. Mathieu, A. Lebrun, S. Andriamanarivo, Lisowski, N. Masurier, S. Zirah, Y. K. Kang, J. Martinez, L. T. Maillard, Chem. Eur. J. 2014, 20, 6713-6720) all the amide protons signals were strongly downfield, i.e. from 8.87 to 10.13 ppm. Such a strong NH deshielding (>9 ppm) has been recognized as a structural marker related to the formation of a C9 hydrogen-bonding pattern. (C. Bonnet; B. Legrand, J. L. Bantignies, N. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664-8669) In addition, 3J(NH,γCH) values <6 Hz (5.3±0.3 Hz) were typical of ϕ values around −60° as expected for a C.sub.9-helix. Further evidences of C.sub.9-helical folding came from the analysis of the 2D-ROESY spectra, which revealed characteristic medium sequential NH(i)/γCH(i−1) and weak γCH(i−1)/γCH(i) correlations. Many weak NH(i)/γCH(i−1), NH(i)/γCH(i−1) and γCH(i−1)/δOH(i) NOE connectivities recognized as structural markers of the ATC helix were also visible for 3 (FIG. 16/A-B). (C. Bonnel, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664-8669) NOEs were used as restraints for NMR solution structure calculations of 3 using a simulated annealing protocol with AMBER 16. Unambiguous 99 distance restraints were introduced to generate an ensemble of 15-lowest energy structures in water that converged toward a well-defined C.sub.9-helix in which all the cationic lateral chains were distributed along a single face (FIG. 16/C). (C. Bonnel, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664-8669)

[0160] FTIR experiments also confirmed the amide hydrogen bonding state of 3 in water. The amide I frequencies provide unambiguous structural indicators of the H-bond network for ATC-containing oligomers. (C. Bonnet, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org, Biomol. Chem. 2016, 14, 8664-8669) The band at 1618 cm.sup.−1 is attributed to the bound ATC C═O. No band is observed around 1645 cm.sup.−1, which confirms that most of the ATC carbonyls is involved in hydrogen-bonds.

[0161] Taking all together, the NMR, FT-IR and CD data were strong evidences of the facially amphiphilic morphology of the designed γ-peptides.

[0162] Evidences of the Facially Amphiphilic Morphology of the Oligomer 4:

[0163] The far-UV CD spectrum of 4 was recorded in water (pH 6.0) at 25 μM between 200 and 300 nm. With two minima at 208 and 220 nm and a strong maximum at 265 nm, the CD signature is consistent with a C.sub.9-helical folding. (C. Bonnet, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664-8669) In addition, the molar ellipticity value per residue (73600 deg.Math.cm.sup.−2.Math.dmol.sup.−1) dmol.sup.−1 for 3 at 265 nm) was similar to the previously value (74000 deg.Math.cm.sup.−2.Math.dmol.sup.−1) reported for helical ATC-oligomers in water.

[0164] NMR analyses of 4 were conducted in H.sub.2O/D.sub.2O (9:1), pH 6.5. As previously observed on ATCs-containing oligomers, (C. Bonnel, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664-8669; B. Legrand, L. Mathieu, A. Lebrun, S. Andriamanarivo, V. Lisowski, N. Masurier, S. Zirah, Y, K. Kang, J. Martinez, L. T. Maillard Chem. Eur. J. 2014, 20, 6713-6720) all the amide protons signals were strongly downfield, i.e. from 8.76 to 10.13 ppm. Such a strong NH deshielding (9 ppm) has been recognized as a structural marker related to the formation of a C9 hydrogen-bonding pattern. In addition, 3J(NH,γCH) values <6 Hz (5.3±0.3 Hz) were typical of ϕ values around −60′ as expected for a C.sub.9-helix. Further evidences of C.sub.9-helical folding came from the analysis of the 2D-ROESY spectra, which revealed characteristic medium sequential NH(i)/γCH(i−1) and weak γCH(i−1)/γCH(i) correlations.

[0165] FTIR experiments also confirmed the amide hydrogen bonding state of 4 in water. The amide I frequencies provide unambiguous structural indicators of the H-bond network for ATC-containing oligomers. (C. Bonnet, B. Legrand, J. L. Bantignies, H. Petitjean, J. Martinez, N. Masurier, L. T. Maillard, Org. Biomol. Chem. 2016, 14, 8664-8669) The band at 1618 cm.sup.−1 is attributed to the bound ATC C═O. No band is observed around 1645 cm.sup.−1, which confirms that most of the ATC carbonyls is involved in hydrogen-bonds.

[0166] Taking all together, the NMR, FT-IR and CD data were strong evidences of the facially amphiphilic morphology of 4.

[0167] Evidences of the helical conformation of the oligomer 5:

[0168] The helical shape of 5 was confirmed by CD and FT-IR experiments. 1/the CD signatures and the molar ellipticity values per residue were identical to those of 3 and 4. 2/The FT-IR spectrum in the 1000-2000 cm.sup.−1 region was readily similar to those of 3 and 4 without any band around 1645 cm.sup.−1 as expected for folded oligomers.

[0169] Table 7 represents Coupling Constants .sup.3J(NH, .sup.γCH) of 3, 4, 6, 7, 8 and 9 (in Hz). Values were measured in H.sub.2O/D.sub.2O (pH 6.5) for 3, 4 and 5 and in CD.sub.3CH for 6, 7, 8 and 9.

TABLE-US-00008 TABLE 7 3 4 6 7 8 9 Residue (283 K) (283 K) (278 K) (278 K) (278 K) (278 K) Res. 1 5.6 5.5 7.0 7.0 7.0 6.9 Res. 2 5.4 5.4 5.0 0 5.1 5.0 Res. 3 5.2 5.3 5.8 6.1 5.1 5.9 Res. 4 5.3 5.1 5.8 o 6.6 5.0 Res. 5 5.0 5.7 6.0 o 5.8 5.0 Res. 6 5.0 4.9 6.0 o 5.1 5.0 Res. 7 5.1 5.2 6.0 o 6.6 5.0 Res. 8 5.2 4.7 6.0 6.1 6.2 5.6 Res. 9 5.9 4.9 6.9 5.1 6.6 5.6 Res. 10 5.2 o 5.6 Res. 11 5.1 o 6.3 Res. 12 6.2 6.6 6.3

[0170] Table 8 represents Inter-residue NOE correlations observed in the ROESY spectrum of (3) and (4) in H.sub.2O/D.sub.2O (9:1) pH 6.5 at 283 K.

TABLE-US-00009 TABLE 8 Compound 3 Compound 4 NOE correlations Intensity NOE correlations Intensity Type Ac-2•NH w Ac-2•NH w Long range 1•NH-2•NH w 1•NH-2•NH nd Sequential 1•Hγ-2•NH m 1•Hγ-2•NH m Sequential 1•Hγ-2•Hγ w 1•Hγ-2•Hγ nd Sequential 1•Hγ-2•Hδ w 1•Hγ-2•Hδ overlap Sequential 1•Hδ-2•NH w 1•Hδ-2•NH w Sequential 1•Hε-2•NH w 1•Hε-2•NH nd Sequential 2•NH-3•NH w 2•NH-3•NH nd Sequential 2•Hγ-3•NH m 2•Hγ-3•NH m Sequential 2•Hγ-3•Hγ w 2•Hγ-3•Hγ nd Sequenti al 2•Hγ-3•Hδ w 2•Hγ-3•Hδ overlap Sequential 2•Nδ-3•NH w 2•Nδ-3•NH overlap Sequential 2•Hγ-3•CH.sub.3 w 2•Hγ-3•CH.sub.3 nd Sequential (thiazole) (thiazole) 3•Hγ-4•NH w 3•Hγ-4•NH nd Sequential 3•Hγ-4•Hγ m 3•Hγ-4•Hγ m Sequential 3•Hγ-4•Hδ w 3•Hγ-4•Hδ overlap Sequential 3•Hδ-4•NH w 3•Hδ-4•NH overlap Sequential 3•Hγ-4•NH w 3•Hγ-4•NH overlap Sequential 3•Hγ-4•CH.sub.3 w 3•Hγ-4•CH.sub.3 nd Sequential (thiazole) (thiazole) 4•NH-5•NH w 4•NH-5•NH nd Sequential 4•Hγ-5•NH m 4•Hγ-5•NH m Sequential 4•Hδ-5•NH w 4•Hδ-5•NH w Sequential 4•Hε-5•NH w 4•Hε-5•NH w Sequential 4•Hγ-5•Hγ w 4•Hγ-5•Hγ nd Sequential 4•Hγ-5•Hδ w 4•Hγ-5•Hδ overlap Sequential 5•NH-6•NH w 5•NH-6•NH nd Sequential 5•Hγ-6•NH m 5•Hγ-6•NH m Sequential 5•Hγ-6•Hγ w 5•Hγ-6•Hγ nd Sequential 5•Hγ-6•Hδ w 5•Hγ-6•Hδ overlap Sequential 5•Hδ-6•NH w 5•Hδ-6•NH overlap Sequential 5•Hγ-6•CH.sub.3 w 5•Hγ-6•CH.sub.3 nd Sequential (thiazole) (thiazole) 6•NH-•NH w 6•NH-7•NH nd Sequential 6•Hγ-7•NH m 6•Hγ-7•NH m Sequential 6•Hγ-7•Hγ w 6•Hγ-7•Hγ overlap Sequential 6•Hγ-7•Hδ w 6•Hγ-7•Hδ overlap Sequential 6•Hδ-7•NH w 6•Hδ-7•NH overlap Sequential 6•Hγ-7•CH.sub.3 w 6•Hγ-7•CH.sub.3 nd Sequential (thiazole) (thiazole) 7•NH-8•NH w 7•NH-8•NH nd Sequential 7•Hγ-8•NH m 7•Hγ-8•NH m Sequential 7•Hγ-8•Hγ w 7•Hγ-8•Hγ nd Sequential 7•Hγ-8•Hδ w 7•Hγ-8•Hδ overlap Sequential 7•Hδ-8•NH w 7•Hδ-8•NH w Sequential 7•Hε-8•NH w 7•Hε-8•NH nd Sequential 8•NH-9•NH nd 8•NH-9•NH nd Sequential 8•Hγ-9•NH m 8•Hγ-9•NH m Sequential 8•Hγ-9•Hγ nd 8•Hγ-9•Hγ nd Sequential 8•Hγ-9•Hδ w 8•Hγ-9•Hδ overlap Sequential 8•Hδ-9•NH w 8•Hδ-9•NH overlap Sequential 8•Hγ-9•CH.sub.3 w 8•Hγ-9•CH.sub.3 nd Sequential (thiazole) (thiazole) 9•NH-NH.sub.2 w 9•NH-10•NH nd Sequential 9•Hγ-NH.sub.2 w 9•Hγ-10•NH m Sequential 9•Hδ-NH.sub.2 w 9•Hγ-10•NH overlap Sequential 9•Hγ-10•NH overlap Sequential 10•NH-11•NH nd Sequential 10•Hγ-11•NH m Sequential 10•Hδ-11•NH w Sequential 10•Hγ-11•Hγ nd Sequential 11•NH-12•NH nd Sequential 11•Hγ-12•NH m Sequential 11•Hγ-12•Hγ nd Sequential 12•NH-NH.sub.2 nd Sequential 12•Hγ-NH.sub.2 w Sequential

[0171] Observed NOE connectivities that could not be attributed unambiguously are shown below for compound 4:

##STR00070##

[0172] FIGS. 13A-13G represent FT-IR spectra (1000-2000 cm-1) of oligomers (3), (4), (5), (6), (7), (8) and (9) in water at 20° C., respectively.

Table 11 represents band positions, band intensities, band widths and band areas in the region of 1000-2000 cm.sup.−1.

TABLE-US-00010 TABLE 11 Absorption Wave- Intensity Width Area Compounds bands numbers (a.u.) (a.u) (a.u) Compound 3 1 (TFA C-F) 1147 0.0041 27.9 0.207 TFA salt 2 (TFA C-F) 1198 0.0072 16.0 0.206 3 1321 0.0007 76.8 0.098 4 1452 0.0012 28.0 0.058 5 1529 0.0014 26.8 0.068 6 1560 0.0020 20.2 0.073 7 1617 0.0027 31.0 0.151 8 1678 0.0030 22.7 0.124 Compound 4 1 (TFA C-F) 1147 0.0046 25.6 0.208 TFA salt 2 (TFA C-F) 1198 0.0079 16.0 0.225 3 1293 0.0003 73.7 0.048 4 1340 0.0006 33.3 0.035 5 1384 0.0003 9.4 0.005 6 1451 0.0011 33.7 0.067 7 1532 0.0015 29.9 0.081 8 1562 0.0018 19.3 0.062 9 1618 0.0028 32.2 0.158 10 1678 0.0032 23.1 0.132 Compound 5 1 (TFA C-F) 1147 0.0040 21.6 0.209 TFA salt 2 (TFA C-F) 1198 0.0070 16.1 0.201 3 11332 0.0008 54.5 0.080 4 1451 0.0012 30.8 0.066 5 1540 0.0018 40.3 0.132 6 11562 0.0013 16.6 0.039 7 1619 0.0033 32.1 0.190 8 11678 0.0031 21.4 0.121 Compound 6 1 (TFA C-F) 1147 0.0046 21.5 0.177 TFA salt 2 (TFA C-F) 1198 0.0076 15.8 0.213 3 1347 0.0009 40.0 0.066 4 1448 0.0014 26.0 0.067 5 1470 0.0011 9.2 0.018 6 1529 0.0020 26.4 0.094 7 1562 0.0030 18.8 0.102 8 1616 0.0039 19.2 0.200 9 1678 0.0037 21.4 0.140 Compound 7 1 (TFA C-F) 1147 0.0053 28.5 0.269 TFA salt 2 (TFA C-F) 1198 0.0088 16.4 0.258 3 1343 0.0009 46.8 0.075 4 1456 0.0017 29.6 0.091 5 1526 0.0018 21.6 0.070 6 1561 0.0033 20.5 0.120 7 1616 0.0034 27.1 0.161 8 1678 0.0039 22.5 0.156 Compound 8 1 (TFA C-F) 1147 0.0041 28.1 0.207 TFA salt 2 (TFA C-F) 1198 0.0072 16.0 0.205 3 1322 0.0007 80.5 0.102 4 1435 0.0005 12.0 0.010 5 1458 0.0010 24.2 0.045 6 1533 0.0016 30.1 0.083 7 1562 0.0017 18.8 0.057 8 1617 0.0027 31.4 0.153 9 1678 0.0031 22.7 0.124 Compound 9 1 (TFA C-F) 1147 0.0034 43.7 0.158 TFA salt 2 (TFA C-F) 1198 0.0060 26.2 0.169 3 1330 0.0008 125.4 0.108 4 1452 0.0011 48.3 0.058 5 1514 0.0006 27.4 0.017 6 1556 0.0022 44.1 0.104 7 1625 0.0040 51.5 0.219 8 1677 0.0038 34.5 0.140

Example 3 Biological Properties

[0173] Minimal Inhibitory Concentration (MIC) Values and Minimal Bactericidal Concentration (MBCs)

[0174] Minimal inhibitory concentration (MIC) values and minimal bactericidal concentration (MBCs) values for ATC-peptides 1-9 were determined against both Gram-positive (Bacillus subtilis, Staphylococcus aureus, Enterococcus faecalis) and Gram negative (Escherichia coli, Pseudomonas aeruginosa) bacteria as well as a yeast (Candida albicans). Experiments were conducted in triplicate. For B. subtilis, compounds were tested against vegetative cells and spores, which are particularly resistant to the action of antimicrobial agents. MIC and MBCs values are shown Table 12. In addition, haemolytic properties of 1-9 were tested.

[0175] The scrambled sequence 5 was less active than its amphiphilic counterpart 4.

TABLE-US-00011 TABLE 12 B. subtilis S. aureus E. faecalis E. coli P. aeruginosa C. albicans Sequence ATCC6633.sup.[a] ATCC6538.sup.[a] ATCC29121.sup.[a] ATCC8739.sup.[a] ATCC9027.sup.[a] ATCC10231.sup.[a] HD.sub.50.sup.[b] 1 >150 (>150) >150 (>150) >150 (>150) >150 (>150) >150 (>150) >150 (>150) >100 2 30 (30) >150 (>150) >150 (>150) >150 (>150) >150 (>150) 62.5 (130) >100 3 0.8 (0.8) >150 (>150) >150 (>150) 5.2 (7.3) 42 (83) 10.4 (10.4) >100 4 0.5 (0.5) 26 (57) >150 (>150) 1.6 (1.6) 3.9 (5.2) 3.7 (3.7) >100 5 0.8 (nd) 100 (nd) >150 (nd) 5.2 (nd) 100 (nd) 50 (nd) HD.sub.10 = 62.5 6 1.3 (1 8) 5.2 (5.2) 6.2 (6.2) 8.3 (8.3) 6.2 (6.2) 6.2 (6.2)  23 7 4.2 (6.2) 16.7 (25) 10.4 (12.5) 14.6 (16.5) 14.6 (19) 25 (25) >100 8 0.5 (0.5) 14.6 (16.5) 100 (>100) 0.8 (0.8) 54 (100) 9.4 (12.5) >100 9 0.6 (0.8) 3.1 (7.8) 20.8 (25) 1.8 (2.3) 4.2 (4.7) 6.2 (6.2) >100

[0176] [a] Minimal inhibitory concentration (MIC) values in μM for ATC-peptides 1-9. Minimal bactericidal concentration (MBCs) values in μM are indicated in bracket [b] dose required to lyse 50% of the red blood cells (HD50) are in μM.

[0177] Surface electron microscopy (SEM) experiments: oligomer 9 was evaluated for its impact on E. coli morphology by surface electron microscopy (SEM). In order to define the best incubation period to observed antimicrobial effects, time-kill study was conducted over 2 h incubation at 37° C. The average log reduction of the viable cell count ranged between 0.95 and 4.73 log.sub.10 cfu/ml on incubating the bacteria for 2 h at the MIC and 8×MIC. Significant decrease of the growth rate was observed between 40 to 60 min at 4× and 8×MIC. TEM experiments were performed after 60 min contact between bacteria cells and compound 9. The untreated E. coli cells were about 2.0 μm long and displayed a smooth and intact surface (FIG. 18 A-C). After incubation with 8×MIC of peptide 9, the bacteria shortened to as little as 1.3 μm and appeared more compact indicating that the bacteria were not able to grow to maximum length. The cells exhibited increased region of cellular aggregation. Beside these changes of morphology, the cells showed blisters (FIG. 19) and protruding vesicles on their surface (FIG. 18 D-I). In addition, whereas there were no fragments for control untreated bacteria, numerous spherical elements whose diameters were lower than 0.1 μm were observed around bacteria, the number of which increasing with the peptide concentration. Despite some dispersion in size, such fragments, probable microsomes, were classically reported with other AMPs associated with membrane permeation and/or depolarization. [M. Hartmann, M. Berditsch J. Hawecker, F. Ardakani, D. Gerthsen, A. S. Ulrich, Antimicrob. Agents Chemother. 2010, 54, 3132-3142 b/ E. Duval, C, Zatylny, M. Laurencin, M. Baudy-Floc'h, J. Henry, Peptides 2009, 30, 1608-1612.] Finally, at supra-MIC numerous lysed cells were observed (FIG. 19).

[0178] This work illustrates the potential of compounds of formula A as scaffold for the development of antibacterial and antifungal compounds.

[0179] Procedure for Antimicrobial Activity Measurements:

[0180] the antimicrobial performances of oligomers antimicrobial activity were determined on three Gram positive strains (Bacillus subtilis ATCC6633, Staphylococcus aureus ATCC6538 and Enterococcus faecalis ATCC29121), two Gram negative strains (Escherichia coli ATCC8739 and Pseudomonas aeruginosa ATCC9027) and one fungal strain (Candida albicans ATCC10231). Each bacterial strain was allowed to grow overnight on Trypto-Caseine-Soja agar (TSA, Difco) at 37° C., C. albicans was allowed to grow 48 h on a sabouraud medium (Difco) at 20-25° C. A fresh suspension at 10.sup.8 CFU.Math.mL.sup.−1 was then prepared by inoculating the micro-organisms in a Tryptone-Sel solution. Concentration was monitored by measuring transmitted light at 620 nm or with the Mac Farland turbidity standard (Mac Farland=0.5≈10.sup.8 CFU.Math.mL.sup.−1). Each suspension was then diluted in a doubly strong Mueller-Hinton (MH, Difco) broth to 106 CFU.Math.mL-1. Two-fold serial dilutions (100 μL) of oligomers in sterile water (pH adjusted between 7.4 and 7.7 with HCl and NaOH solutions) were mixed with microbial inoculum (100 μL) in NUNC sterile clear polystyrene flat-bottom 96-well plates. A 1/1 v/v oligomer solution/water mixture was used a negative control and a 1/1 vv water/microbial inoculum mixture was used a positive control. Plates were then incubated 24 h at 37° C. for bacteria and 48 h at 25° C. for C. albicans. Minimum Inhibitory Concentration (MIC) was determined as the lowest concentration inhibiting the growth of each micro-organism. After MIC determination, each well was transferred to a Petri dish containing MH agar, using a Mic-2000 inoculator (Dynatech) and was incubated 24 h at 37° C. for bacteria and 48 h at 25° C. for C. albicans. Minimum Bactericidal Concentration (MBC) was determined as the lowest concentration that prevent the growth of more than one colony. Each assay was performed in a triple duplicate for each strain.

[0181] Time-kill study: the antimicrobial kinetics of 9 were evaluated at 0, 1.8 μM (MIC), 7.2 μM (4×MIC) and 14.4 μM (8×MIC) and time intervals of 0, 10, 20, 40, 60 and 120 min (FIG. 17).

[0182] Procedure for measurements of hemolytic activity: Human red blood cells (hRBCs) were washed multiple times with phosphate-buffered saline (PBS) until a clear supernatant was obtained. The hRBCs suspension was made in PBS with a Packed Cell Volume of 5%, Two-fold serial dilutions (50 μL) of oligomers in sterile water (pH adjusted between 7.4 and 7.7 with HCl and NaOH solutions) were mixed with hRBCs suspension (50 μL) in clear polystyrene optical-bottom 96-well plates which were filmed and incubated for 1 h at 37° C. A 1/1 vv hRBCs solution/PBS mixture was used a negative control and a 1/1 vv hRBCs solution/1% (TRIS 50 mM pH=8.0+1% SDS) mixture was used a positive control for 100% hemolysis. The mixture was then centrifuged at 1500 g for 10 min at 5° C. Next, 50 μL of the supernatant was transferred into a second plate, and the absorbance was read at 490 nm using a BioRad iMark plate reader. The hemolysis percentage was calculated by the formula % hemolysis=[Absorbance (sample)−Absorbance (negative control)]/[Absorbance (positive control)−Absorbance (negative control)]×100%. Each assay was performed in a double duplicate. Hemolytic activity was determined or estimated with the Hemolytic Concentration leading to 50% of lysis of hRBCs (HC50).

[0183] Procedure for Surface electron microscopy: PBS washed cells were fixed with 2.5% glutaraldehyde in PHEM buffer, pH 7.2 for an hour at room temperature, followed by washing in PHEM buffer. Fixed samples were dehydrated using a graded ethanol series (30-100%), followed by 10 minutes in graded Ethanol-Hexamethyldisilazane, And then Hexamethyldisilazane alone. Subsequently, the samples were sputter coated with an approximative 10 nm thick gold film and then examined under a scanning electron microscope (Hitachi 54000, at CoMET, MRI-RIO Imaging, Biocampus, INM Montpellier France) using a lens detector with an acceleration voltage of 10 KV at calibrated magnifications.