The present disclosure relates to novel compounds and pharmaceutical compositions thereof which are useful as inhibitors of proteasomes. The compounds provided herein have improved proteasome potency and selectivity, and increased aqueous solubility, and are useful in treating various conditions or diseases associated with proteasomes.

The present invention relates to use of peptides as a therapeutic agent, wherein it has been confirmed that the peptides of the present invention significantly inhibit the activity of T cells and the differentiation of T helper 17 cells (Th17 cells), which are associated with autoimmune disease, and have remarkable effects of treating and improving arthritis in an animal model of arthritis. Therefore, the peptides may be used as an active ingredient in therapeutic agents for various autoimmune diseases such as bone disease, inflammatory disease or rheumatoid arthritis.

The present invention relates to a GABA.sub.A receptor-binding peptide comprising an amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5, wherein the amino acid residue X.sub.1 is histidine, arginine, threonine, L-cyclohexyl-alanine, 2-flouro-L-phenylalanine or 3-methyl-L-histidine; X.sub.2 is threonine, N-methyl-threonine, proline, leucine, isoleucine or phenylalanine; X.sub.3 is tryptophan, N-methyl-tryptophan, serine, threonine or proline; X.sub.4 is glutamine, proline, lysine, tyrosine, alanine, glycine or absent; and X.sub.5 is lysine, glutamic acid, aspartic acid, threonine, alanine, glycine or absent. In particular, the GABA.sub.A receptor-binding peptides of the present invention have amino acid sequences selected from SEQ ID NOs: 1 to 15. These peptides were tested and validated using electrophysiological recordings on the human GABA.sub.A receptor comprising of the following subunits .sub.1.sub.3.sub.2 and used in the preparation of a neuroactive pharmaceutical composition, in improving sperm motility or in labeling of biomolecules.

The present invention discloses compounds of Formula I or pharmaceutically acceptable salts, esters, or prodrugs thereof:

##STR00001##

which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

The invention is directed to the use of at least one peptide of formula: X-(Xaa.sub.1).sub.n-Pro*-(Xaa.sub.2).sub.m-Y (I) With: -n=0, 1 or 2; -m=0 or 1 and if m=0 then n0 -Xaa.sub.1 is: -An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val, V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I), Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivatives thereof; -A polar aminoacid selected from Serine (Ser, S), Threonine (Thr, T), Tyrosine (Tyr, Y), Asparagine (Asn, N), Glutamine (Gln, Q) and analogues and derivatives thereof; -or Glycine (Gly, G); When n=2 the two aminoacids Xaa.sub.1 can be the same or different; -Xaa.sub.2 is: -An hydrophobic aminoacid selected from Alanine (Ala, A), Valine (Val, V), Methionine (Met, M), Leucine (Leu, L), Isoleucine (Ile, I), Phenylalanine (Phe, F), Proline (Pro, P) and analogues and derivatives thereof; -A basic aminoacid selected from Arginine (Arg, R), Lysine (Lys, K) and Histidine (His, H) and analogues and derivatives thereof; -Glycine (Gly, G) or Serine (Ser, S); -At the N terminal end of the peptide, X is selected from H, COR.sub.1 and SO.sub.2R.sub.1; -At the C terminal end of the peptide, Y is selected from OH, OR.sub.1, NH.sub.2, NHR.sub.1 or NR.sub.1R.sub.2, R.sub.1 and R.sub.2 being independently from each other, selected from an alkyle, aryle, aralkyle, alkylaryl, alkoxy and aryloxy group, that can be linear, branched, cyclic, poly-cyclic, non-saturated, hydroxylated, carbonylated, phosphorylated and/or sulphured, with the possibility to have in said group skeleton a O, S and/or N heteroatom; -Pro* corresponding to a Proline, an analogue or derivative thereof; Excluding the peptides where X=H and Y=OH, for a non therapeutical cosmetic pro-pigmenting treatment of skin. The invention also encompasses new tripeptides of formula (I) suitable for a non therapeutical cosmetic treatment of skin.

A water-soluble peptide fluorescence material having a structure of formula (I): ##STR00001## In formula (I), n is an integer greater than or equal to 1, R.sub.1 is independently selected from hydrogen or a nitrogen-containing functional group, R.sub.2 is independently selected from hydrogen or alkyl, and A.sub.1 is polymerized by at least one amino acid monomer and having a structure of formula (II): ##STR00002## In formula (II), m is an integer greater than or equal to 1, and R.sub.3 in each of the amino acid monomers of A.sub.1 is independently selected from hydrogen, alkyl, aralkyl, alkylthioaalkyl, hydroxyaralky, heteroaralkyl, carboxylalkyl, or guanidinylalkyl. A.sub.2 is OR.sub.5 or N(R.sub.4).sub.2, and R.sub.4 is independently selected from hydrogen, alkyl, aralkyl, alkylthioaalkyl, hydroxyaralky, heteroaralkyl, carboxylalkyl, guanidinylalkyl, monoglycosyl, biglycosyl, or oligosaccharyl, and R.sub.5 is hydrogen, alkyl, aralkyl, alkylthioaalkyl, hydroxyaralky, heteroaralkyl, carboxylalkyl, or guanidinylalkyl.

Novel compounds and methods for the inhibition of biological barrier permeability and for the inhibition of peptide translocation across biological barriers are identified. Assays for determining modulators of biological barrier permeability and for peptide translocation across biological barriers are provided. Methods for treating diseases relating to aberrant biological barrier permeability and peptide translocation across biological barriers are provided. Such diseases include celiac disease, necrotizing enterocolitis, diabetes, cancer, inflammatory bowel diseases, asthma, COPD, excessive or undesirable immune response, gluten sensitivity, gluten allergy, food allergy, rheumatoid arthritis, multiple sclerosis, immune-mediated or type 1 diabetes mellitus, systemic lupus erythematosus, psoriasis, scleroderma and autoimmune thyroid diseases.

Provided herein are tripeptide epoxy ketone protease inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula (X):

##STR00001##

and pharmaceutically acceptable salts and compositions including the same. The compounds and compositions provided herein may be used, for example, in the treatment of diseases including inflammation and neurodegenerative disease.

Processes for preparing compounds of Formula (1) and Formula (2) are described, wherein X, Y, Z, R.sub.1-R.sub.7, L and n are defined herein. Intermediates useful in the preparation of the compounds of Formula (1) and Formula (2) are also described. ##STR00001##

This disclosure features compounds that are useful as pro-drugs of epoxy ketone protease inhibitors.