Therapeutic peptide-based constructs

Abstract

The present invention relates generally to small peptide-based constructs, including derivatized constructs, and their therapeutic uses. The sequences of these constructs are based on a reverse subsequence derived from Domain II of bactericidal/permeability-increasing protein (BPI).

1 - 16 . (canceled)  
     
     
         17 . A pharmaceutical composition comprising a derivatized peptide-based construct of 8-15 amino acid moieties in length having heparin binding, heparin neutralizing, endothelial cell proliferation inhibiting, antiangiogenic, LPS binding, LPS neutralization, or antimicrobial properties comprising: 
 a sequence having the formula:      R 1 -α-χ-χ-α-χ-β-χ-α-R    wherein,    α is a hydrophilic basic amino acid moiety that is any one of lysine, arginine, histidine, ornithine, diaminobutyric acid, citrulline, or para-amino phenylalanine;    β is a hydrophilic neutral amino acid moiety that is any one of asparagine, glutamine, serine, threonine, tyrosine, hydroxyproline, or 7-hydroxy-tetrahydroisoquinoline carboxylic acid;    χ is a hydrophobic amino acid moiety that is any one of alanine, naphthylalanine, biphenylalanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, cyclohexylalanine, amino-isobutyric acid, norvaline, norleucine, tert-leucine, tetrahydroisoquinoline carboxylic acid, pipecolic acid, phenylglycine, homophenylalanine, cyclohexylglycine, dehydroleucine, 2,2-diethylglycine, 1-amino-1-cyclopentane carboxylic acid, 1-amino-1-cyclohexane carboxylic acid, amino-benzoic acid, amino-naphthoic acid, γ-amino butyric acid, beta-alanine, difluorophenylalanine, fluorophenylalanine, nipecotic acid, α-aminobutyric acid, thienyl-alanine, or t-butyl-glycine;    R is an amino acid moiety that is any one of -χ, -χ-α, -χ-α-χ, χ-α-χ-β, -χ-α-χ-β-χ, -χ-α-χ-β-χ-α, -χ-α-χ-β-χ-α-χ, -χ-α-χ-χ-α-χ, —NH 2 , -χ-NH 2 , -χ-α-NH 2 , -χ-α-χ-NH 2 , -χ-α-χ-β-NH 2 , -χ-α-χ-β-χ-NH 2 , -χ-α-χ-β-χ-α-NH 2 , -χ-α-χ-β-χ-α-χ-NH 2 , or -χ-α-χ-χ-α-χ-NH 2 ; and    wherein,    R 1  is any one of R 2 —CH 2 , R 2 —CH 2 —CO—, R 2 —CO—, R 2 —SO 2 , or R 2 —PO z -; 
 wherein, 
 y=0−3,  
 z=1−4;  
 
   R 2  is a hydrophobic moiety that is any one of a cyclic molecule having at least 3 carbon atoms, a heterocyclic molecule having at least 3 atoms, a functionalized cyclic molecule having at least 3 carbon atoms, or a functionalized heterocyclic molecule having at least 3 atoms, and    a pharmaceutically acceptable diluent, adjuvant, or carrier.    
     
     
         18 . A pharmaceutical composition comprising a composition of 8-15 amino acid moieties consecutively linked by peptide bonds, said composition having one or more heparin binding properties and comprising a sequence of the formula:  
         R 1 -KLFR(naph-A)QAR 3    R 1  is any one of R 2 —CH 2 , R 2 —CH 2 —CO—, R 2 —CO—, R 2 —SO y -, or R 2  PO z -; 
 wherein, 
 y=0−3,  
 z=1−4;  
 
   R 2  is a hydrophobic moiety that is any one of a cyclic molecule having at least 3 carbon atoms, a heterocyclic molecule having at least 3 atoms, a functionalized cyclic molecule having at least 3 carbon atoms, or a functionalized heterocyclic molecule having at least three atoms;    wherein R 3  is any one of K, K(naph-A), K(naph-A)K, K(naph-A)KG, K(naph-A)KGS, K(naph-A)KGSI, K(naph-A)KGSIK or K(naph-A)KGSIKI;    wherein the carboxyl terminal group is amidated or nonamidated, 
 and, optionally, comprising at least one conservative substitution of amino acid moieties, and  
   a pharmaceutically acceptable diluent, adjuvant, or carrier.    
     
     
         19 . The pharmaceutical composition of  claim 18  wherein the composition comprises two or more conservative substitutions of amino acid moieties.  
     
     
         20 . The pharmaceutical composition of  claim 17  or  18  wherein the peptide-based construct or composition has heparin neutralizing properties.  
     
     
         21 . The pharmaceutical composition of  claim 17  or  18  wherein the peptide-based construct or composition has endothelial cell proliferation inhibiting properties.  
     
     
         22 . The pharmaceutical composition of  claim 17  or  18  wherein the peptide-based construct or composition has anti-angiogenic properties.  
     
     
         23 . The pharmaceutical composition of any one of  claims 17  to  22  wherein the first two amino-terminal amino acid moieties of the peptide-based construct or composition are D-amino acid moieties and the last two carboxy-terminal amino acid moieties of the peptide-based construct or composition are D-amino acid moieties.  
     
     
         24 - 34 . (canceled)