Compositions and methods for combinatorial drug discovery in nanoliter droplets are described. Novel synergistic agents that increase efficacy of antibiotic agents to treat bacterial infection are disclosed.

Compositions and methods for combinatorial drug discovery in nanoliter droplets are described. Novel synergistic agents that increase efficacy of antibiotic agents to treat bacterial infection are disclosed.

The present disclosure is directed to a peptide of formula (I), or a pharmaceutically acceptable salt thereof, and uses thereof: R.sup.1—C—R—X.sup.1—X.sup.2—P—X.sup.3—X.sup.4—X.sup.5—X.sup.6—C—R.sup.2 (I) wherein X.sup.1, X.sup.3, X.sup.5, and X.sup.6 is an amino acid residue selected from the group consisting of serine, alanine, valine, leucine, isoleucine and glycine; X.sup.2 is alanine, arginine or lysine; X.sup.4 is glutamic acid or aspartic acid; R.sup.1 is selected from the group consisting of S, HS, GHS, PGHS, APGHS, EAPGHS, SEAPGHS, SSEAPGHS, PSSEAPGHS, DPSSEAPGHS and IDPSSEAPGHS, or R.sup.1 is absent; and R.sup.2 is selected from the group consisting of S, SS, SSK, SSKF, SSKFS, SSKFSW, SSKFSWD, SSKFSWDE, SSKFSWDEY, SSKFSWDEYE, SSKFSWDEYEQ, SSKFSWDEYEQY, SSKFSWDEYEQYK, SSKFSWDEYEQYKK, SSKFSWDEYEQYKKE, or R.sup.2 is absent; and wherein the peptide of formula (I), or the pharmaceutically acceptable salt thereof, is a cyclic peptide formed by a disulphide bond between the two cysteine residues.

The present disclosure is directed to a peptide of formula (I), or a pharmaceutically acceptable salt thereof, and uses thereof: R.sup.1—C—R—X.sup.1—X.sup.2—P—X.sup.3—X.sup.4—X.sup.5—X.sup.6—C—R.sup.2 (I) wherein X.sup.1, X.sup.3, X.sup.5, and X.sup.6 is an amino acid residue selected from the group consisting of serine, alanine, valine, leucine, isoleucine and glycine; X.sup.2 is alanine, arginine or lysine; X.sup.4 is glutamic acid or aspartic acid; R.sup.1 is selected from the group consisting of S, HS, GHS, PGHS, APGHS, EAPGHS, SEAPGHS, SSEAPGHS, PSSEAPGHS, DPSSEAPGHS and IDPSSEAPGHS, or R.sup.1 is absent; and R.sup.2 is selected from the group consisting of S, SS, SSK, SSKF, SSKFS, SSKFSW, SSKFSWD, SSKFSWDE, SSKFSWDEY, SSKFSWDEYE, SSKFSWDEYEQ, SSKFSWDEYEQY, SSKFSWDEYEQYK, SSKFSWDEYEQYKK, SSKFSWDEYEQYKKE, or R.sup.2 is absent; and wherein the peptide of formula (I), or the pharmaceutically acceptable salt thereof, is a cyclic peptide formed by a disulphide bond between the two cysteine residues.

It was found that a peptide compound that has an N-substituted-α,α-disubstituted amino acid residue at the N-terminus and containing a dipeptide residue in which the N-substituted-α,α-disubstituted amino acid residue and an N-substituted amino acid residue are linked together, can be efficiently produced by linking an N-unsubstituted-α,α-disubstituted amino acid whose amino group is protected with an electron-withdrawing protecting group to an N-substituted amino acid or a peptide compound having an N-substituted amino acid residue at the N-terminus, and then allowing a substituent-introducing agent to act in the presence of a specific base to selectively introduce a substituent to the amino group at the N-terminus.

Degradation compounds include a cyclic cell penetrating peptide (cCPP) and a degradation construct. The degradation construct includes a degradation moiety and a targeting moiety. The targeting moiety binds a target protein. When the targeting moiety is bound to the target protein, the degradation moiety mediates degradation of the target protein. The cCPP facilitates transfer of the degradation construct into a cell. The degradation compound may further include an exocyclic peptide to enhance endosomal escape of the compound or degradation construct once inside the cell.

Degradation compounds include a cyclic cell penetrating peptide (cCPP) and a degradation construct. The degradation construct includes a degradation moiety and a targeting moiety. The targeting moiety binds a target protein. When the targeting moiety is bound to the target protein, the degradation moiety mediates degradation of the target protein. The cCPP facilitates transfer of the degradation construct into a cell. The degradation compound may further include an exocyclic peptide to enhance endosomal escape of the compound or degradation construct once inside the cell.

The present invention provides peptides of general formula (I) and salts thereof, wherein: R.sub.1 and R.sub.2, taken together, form a birradical linker; and R.sub.2′ is hydrogen; or, alternatively, R.sub.1 is selected from hydrogen, —C(═O)—CH.sub.2—NH—C(═O)—(C.sub.1-C.sub.5)alkyl, and —C(═O)—(C.sub.1-C.sub.20)alkyl; one of R.sub.2 and R.sub.2′ is hydrogen and the other is selected from —C(═O)NR.sub.3R.sub.4, and —C(═O)OH; and R.sub.3 and R.sub.4 are same or different and are selected from hydrogen and (C.sub.1-C.sub.10)alkyl. These peptides are highly efficient in binding and inhibiting FoxP3, being efficient in inhibiting and blocking Treg cell functionality, which make them useful in the treatment of cancer. The present invention also provides constructs comprising the peptide of formula (I) as well as combinations comprising the peptide of formula (I), the construct or both. ##STR00001##

The present invention provides peptides of general formula (I) and salts thereof, wherein: R.sub.1 and R.sub.2, taken together, form a birradical linker; and R.sub.2′ is hydrogen; or, alternatively, R.sub.1 is selected from hydrogen, —C(═O)—CH.sub.2—NH—C(═O)—(C.sub.1-C.sub.5)alkyl, and —C(═O)—(C.sub.1-C.sub.20)alkyl; one of R.sub.2 and R.sub.2′ is hydrogen and the other is selected from —C(═O)NR.sub.3R.sub.4, and —C(═O)OH; and R.sub.3 and R.sub.4 are same or different and are selected from hydrogen and (C.sub.1-C.sub.10)alkyl. These peptides are highly efficient in binding and inhibiting FoxP3, being efficient in inhibiting and blocking Treg cell functionality, which make them useful in the treatment of cancer. The present invention also provides constructs comprising the peptide of formula (I) as well as combinations comprising the peptide of formula (I), the construct or both. ##STR00001##

The invention relates to novel methods for synthesizing amanitin derivatives having a hydroxy group attached to the central tryptophan moiety. The invention furthermore relates to novel amanitin derivatives having a hydroxy group attached to position 4′, 5′ or 7′ of the central tryptophan moiety, novel conjugates of such amanitin derivatives, and pharmaceutical compositions comprising such conjugates.