Therapeutic peptide-based constructs
AssigneeXoma Technology Ltd.
InventorsRoger G. Little II, Jong-Jye Lin, J.G. Kinyua Gikonyo
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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-increasingprotein (BPI).
Claims34
A peptide-based construct of 8-15 amino acid moieties in length having at least one of heparin binding, heparin neutralizing, endothelial cell proliferation inhibiting, or antiangiogenic properties comprising:
- a sequence having the formula:
- 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;
- and
- 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, -NH2, -χ-NH2, -χ-α-NH2, -χ-α-χ-NH2, -χ-α-χ-β-NH2, -χ-α-χ-β-χ-NH2, -χ-α-χ-β-χ-α-NH2, -χ-α-χ-β-χ-α-χ-NH2, or -χ-α-χ-χ-α-χ-NH2.
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:
- KLFR(naph-A)QAR3
- wherein R3 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;
- or
- wherein the carboxyl terminal group is amidated or nonamidated,
- and optionally, at least one conservative substitution of amino acid moieties.
A derivatized peptide-based construct of 8-15 amino acid moieties in length having heparin binding, heparin neutralizing, endothelial cell proliferation inhibiting, or antiangiogenic properties comprising:
- a sequence having the formula:
- R1-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-αχ-χ-α-χ, -NH2, -χ-NH2, -χ-α-NH2, -χ-α-χ-NH2, -χ-α-χ-β-NH2, -χ-α-χ-β-χ-NH2, -χ-α-χ-β-χ-α-NH2, -χ-α-χ-β-χ-α-χ-NH2, or -χ-α-χ-χ-α-χ-NH2;
- and
- wherein,
- R1 is any one of R2—CH2—, R2—CH2—CO—, R2—CO—, R2—SOy—, or R2—POz—;
- wherein,
- y=0-3,
- z=1-4;
- R2 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.
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:
- R1KLFR(naph-A)QAR3
- R1 is any one of R2—CH2—, R2—CH2—CO—, R2—CO—, R2—SOy—, or R2—POz—;
- wherein,
- y=0-3,
- z=1-4;
- R2 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 R3 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.
Dependencies are inferred from the claim text.