Inhibition of pulmonary fibrosis with nutlin-3a and peptides

Abstract

In fibrotic lung fibroblasts, basal levels of p53 protein (and miR-34a) are markedly suppressed, leading to reduced p53-mediated inhibition of uPA and uPAR, or concurrent induction of PAI-1. These changes contribute to excessive FL-fibroblast proliferation and production of extracellular matrix (ECM), and, therefore, pulmonary fibrosis. These processes are reversed by treating the cells, and treating subjects suffering from idiopathic pulmonary fibrosis (IPF) with the small organic molecule nutlin-3a (NTL) or with a peptide, CSP-4 (SEQ ID NO: 1), or variants or derivatives or multimers of this peptide, which increase p53 levels by inhibiting MDM2-mediated degradation of p53 protein. Use of these compounds serves as a new approach to the treatment of IPF, as they restore p53 expression and p53-mediated changes in the uPA-fibrinolytic system in FL-fibroblasts and restrict production and deposition of ECM.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a polypeptide having one or more amino acid sequences consisting of FTTFTVT (SEQ ID NO: 1), the polypeptide further comprising a cap at its N- or C-terminus and in a pharmaceutically acceptable carrier. 
     
     
         2 . The composition of  claim 1 , wherein the polypeptide comprises the cap at its N-terminus. 
     
     
         3 . The composition of  claim 1 , wherein the polypeptide comprises the cap at its C-terminus. 
     
     
         4 . The composition of  claim 1 , wherein the polypeptide comprises the cap at both its N-terminus and C-terminus. 
     
     
         5 . The composition of  claim 1 , wherein the cap comprises an acyl or amido group. 
     
     
         6 . The composition of  claim 1 , wherein the cap comprises a formyl, an alkanoyl having up to 10 carbon atoms, an alkenoyl having up to 10 carbon atoms, alkynoyl having up to 10 carbon atoms, an aroyl, a heteroaroyl, an alkylsulfonyl, an arylsulfonyl, a heteroarylsulfonyl, a substituted alkanoyl having up to 10 carbon atoms, a substituted alkenoyl having up to 10 carbon atoms, a substituted alkynoyl having up to 10 carbon atoms, a substituted aroyl, a substituted heteroaroyl, a substituted alkylsulfonyl, a substituted arylsulfonyl, a substituted heteroarylsulfonyl, a carbamoyl, a thiocarbamoyl, a substituted carbamoyl (R′—NH—CO), a substituted thiocarbamoyl (R′—NH—CS) wherein R′ is alkyl, alkenyl, alkynyl, aryl, heteroaryl, a substituted alkyl having up to 10 carbons, a substituted alkenyl having up to 10 carbons, a substituted alkynyl having up to 10 carbon atoms, a substituted aryl having up to 10 carbon atoms, or a substituted heteroaryl having up to 10 carbon atoms. 
     
     
         7 . The composition of  claim 6 , wherein the cap comprises acetyl, propionyl, butyryl, hex-3-enoyl, hex-5-ynoyl, benzoyl, 1-naphthoyl, 3-pyrroyl, 4-quinoloyl, methanesulfonyl, benzenesulfonyl, sulfanilyl, pyridine-4-sulfonyl, 4-aminobutyryl, 6-hydroxy-hex-3-enoyl, 3-hydroxy-hex-5-ynoyl, 4-chlorobenzoyl or 8-hydroxy-naphth-2-oyl, 2,4-dioxo-1,2,3,4-tetrahydro-3-methyl-quinazolin-6-oyl, 2-aminoethanesulfonyl, 5-dimethylamino-1-naphthalenesulfonyl, 1-methoxy-6-isoquinolinesulfonyl, methyl, ethyl, isopropyl, prop-2-enyl; prop-2-ynyl, hydroxyalkyl, alkoxyalkyl, mercaptoalkyl, alkylthioalkyl, halogenoalkyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkanoylalkyl, carboxyalkyl, carbamoylalkyl, hydroxyalkenyl, alkoxyalkenyl, mercaptoalkenyl, alkylthioalkenyl, halogenoalkenyl, cyanoalkenyl, aminoalkenyl, alkylaminoalkenyl, dialkylaminoalkenyl, alkanoylalkenyl, carboxyalkenyl, carbamoylalkenyl, hydroxyalkynyl, alkoxyalkynyl, mercaptoalkynyl, alkylthioalkynyl, halogenoalkynyl, cyanoalkynyl, aminoalkynyl, alkylaminoalkynyl, dialkylaminoalkynyl, alkanoylalkynyl, carboxyalkynyl, carbamoylalkynyl, phenacyl, 2-benzoylethyl, phenyl, 1-naphthyl, 4-quinolyl, acetyl, butyryl, or benzoyl, 3-quinoloyl. 
     
     
         8 . The composition of  claim 1 , wherein the polypeptide comprises L-amino acids. 
     
     
         9 . The composition of  claim 1 , wherein the polypeptide comprises at least one D-amino acid. 
     
     
         10 . The composition of  claim 1 , wherein the polypeptide further comprises an internalization sequence. 
     
     
         11 . The composition of  claim 1 , wherein the polypeptide is cyclized. 
     
     
         12 . The composition of  claim 1 , wherein the polypeptide is a multimeric polypeptide comprising more than one repeating unit of the amino acid sequence consisting of FTTFTVT (SEQ ID NO: 1). 
     
     
         13 . The composition of  claim 12 , wherein the polypeptide comprises from 2 to 5 repeating units of FTTFTVT (SEQ ID NO: 1). 
     
     
         14 . The composition of  claim 13 , wherein the polypeptide further comprises a spacer polypeptide between one or more of the repeating units. 
     
     
         15 . The composition of  claim 14 , wherein the spacer comprises repeating units of glycine.