Lipid conjugates of therapeutic peptides and protease inhibitors

• US 5,554,728 A
• Filed: 07/23/1991
• Issued: 09/10/1996
• Est. Priority Date: 07/23/1991
• Status: Expired due to Term

• Current Assignee: Chimerix Incorporated
• Original Assignee: NeXstar Pharmaceuticals, Inc. (Gilead Sciences Inc.)
• Inventors: Hostetler, Karl Y., Basava, Channa
• Primary Examiner(s): Scheiner, Toni R.
• Assistant Examiner(s): HUFF, SHEELA JITENDRA
• Application Number:
  US07/734,434
• Time in Patent Office: 1,876 Days
• Field of Search: 530/327-331, 530/345, 514/12-19, 548/535, 562/561
• US Class Current: 530/327
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07C 69/96 Esters of carbonic or haloformic acids
• CPC Class Codes: C07F 9/10 Phosphatides, e.g. lecithin
• CPC Class Codes: C07K 1/006 of peptides containing derivatised side chain amino acids
• CPC Class Codes: C07K 1/1075 by covalent attachment of amino acids or peptide residues
• CPC Class Codes: C07K 1/1077 by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
• CPC Class Codes: C07K 11/00 Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/0205 containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
• CPC Class Codes: C07K 5/06052 Val-amino acid
• CPC Class Codes: C07K 5/06069 Ser-amino acid
• CPC Class Codes: C07K 5/06095 Arg-amino acid
• CPC Class Codes: C07K 5/06113 Asp- or Asn-amino acid
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/081 the side chain containing O or S as heteroatoms, e.g. Cys, Ser
• CPC Class Codes: C07K 5/0823 and Pro-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/1008 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/1016 and aromatic or cycloaliphatic
• CPC Class Codes: C12N 2740/16222 : New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes

Abstract

Compounds wherein therapeutic peptides are covalently linked to phospholipids, glycerides or other membrane-targeting and membrane-anchoring species, and their pharmaceutically acceptable salts, together with processes for their preparation. The targeting technology is applicable to HIV protease inhibitors and a variety of other enzyme inhibitors.

Claims

1. A peptide-lipid conjugate selected from the group consisting of:

##STR7## wherein X represents phosphatidyl-tyrosine;

phosphatidyl-serine;

phosphatidyl-threonine;

phosphatidyl-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;

1-O-acyl-sn-glycero-3-phospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-phospho-O-serine;

1-O-acyl-sn-glycero-3-phospho-O-serine;

1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine;

1-O-acyl-sn-glycero-3-phospho-O-threonine;

1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-diphospho-O-serine;

1-O-acyl-sn-glycero-3-diphospho-O-serine;

1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-diphospho-O-threonine;

1-O-acyl-sn-glycero-3-diphospho-O-threonine;

phosphatidyl ethanolamine-Y;

phosphatidic acid, or phosphatidic acid-Z,

wherein Y is HOOC--(CH₂)_n --COOH;

Z is HO--(CH₂)_n --COOH; and

n=1 to 12;

C represents H, OH, OMe, NH₂, NH--R where R represents C_1-12 alkyl, benzyl, substituted benzyl, (CH₂)_n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H₂ N--(CH₂)_n --COOH, and n=1 to 12.

6. A peptide-lipid conjugate according to claim 1 selected from the group consisting of:

i-Boc-Tyr-Pro-Ile-Gly-DPPE;

DPPA-Ser-Gln-Asn-Tyr-Pro-Ile-Val-NH₂ ;

DPPA-Ser-Gln-Asn-Tyr-Acpnt-Ile-Val-NH₂ ;

DPPE-Succinyl-Ala-Ala-(D-b-Nal)-Pip-OMe;

DPPE-Succinyl-Val-Ser-Gln-Asn-Tyr-Pip-Ile-Val-Gln-NH₂ ;

DMPE-Succinyl-Val-Ser-Gln-Asn-Tyr-Pip-Ile-Val-Gln-NH₂ ;

DMPE-Succinyl-Val-Ser-Gln-Asn-Tyr-Diq-Ile-Val-Gln-NH₂ ;

DPPE-Succinyl-(D-Phe)-(D-a-Nal)-Pip-(L-a-(OH)-Leu)-Val-NH₂ ;

DPPE-Succinyl-Phe(CHOH--CH2N)Phe-Ile-Phe-NH₂ ;

##STR8## X-Phe(CHOH--CH₂ N)Phe-Ile-Phe-NH₂ ; and

X-Phe(CHOH--CH₂ N)Pro-Ile-Val-NH₂,

wherein DMPE is dimyristoyl phosphatidyl ethanolamine;

DPPE is dipalmitoyl ethanolamine; and

DPPA is dipalmitoyl phosphatidic acid; and

Ser(DPP) is dipalmitoyl phosphatidyl serine.

2. A peptide-lipid conjugate selected from the group consisting of:

5(S)-X-Amino-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-Phe-C;

5(S)-X-Amino-4(S)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-C;

5(S)-X-amino-4(S)-hydroxy-6-cyclohexyl-2(R)-(phenylmethyl)hexanoyl-C;

5(S)-X-Amino-4(R)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-Phe-C;

5(S)-X-Amino-4(R)-hydroxy-6-phenyl-2(R)-(phenylmethyl)hexanoyl-Leu-C; and

5(S)-X-amino-4(R)-hydroxy-6-cyclohexyl-2(R)-(phenylmethyl)hexanoyl-C;

wherein

X represents phosphatidyl-tyrosine;

phosphatidyl-serine;

phosphatidyl-threonine;

phosphatidyl-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;

1-O-acyl-sn-glycero-3-phospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-phospho-O-serine;

1-O-acyl-sn-glycero-3-phospho-O-serine;

1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine;

1-O-acyl-sn-glycero-3-phospho-O-threonine;

1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-diphospho-O-serine;

1-O-acyl-sn-glycero-3-diphospho-O-serine;

1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-diphospho-O-threonine;

1-O-acyl-sn-glycero-3-diphospho-O-threonine;

phosphatidyl ethanolamine-Y;

phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH₂)_n --COOH and

Z is HO--(CH₂)_n --COOH; and

n=1 to 12; and

C represents H, OH, OMe, NH₂, NH--R where R represents C_1-12 alkyl, benzyl, substituted benzyl, (CH₂)_n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H₂ N--(CH₂)_n --COOH, and n=1 to 12.

3. A peptide-lipid conjugate selected from the group consisting of:

5(S)-X-Amino-4(S)-hydroxy-6-cyclcohexyl-2(R)-isopropyl-hexanoyl-Ile-C;

5(S)-X-Amino-4(R)-hydroxy-6-cyclcohexyl-2(S)-isopropyl-hexanoyl-Ile-C;

5(S)-X-Amino-4(S)-hydroxy-6-phenyl-2(R)-isopropyl-hexanoyl-Ile-C; and

5(S)-X-Amino-4(R)-hydroxy-6-phenyl-2(S)-isopropyl-hexanoyl-Ile-C;

wherein

X represents phosphatidyl-tyrosine;

phosphatidyl-serine;

phosphatidyl-threonine;

phosphatidyl-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;

1-O-acyl-sn-glycero-3-phospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-phospho-O-serine;

1-O-acyl-sn-glycero-3-phospho-O-serine;

1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine;

1-O-acyl-sn-glycero-3-phospho-O-threonine;

1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-diphospho-O-serine;

1-O-acyl-sn-glycero-3-diphospho-O-serine;

1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-diphospho-O-threonine;

1-O-acyl-sn-glycero-3-diphospho-O-threonine;

phosphatidyl ethanolamine-Y;

phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH₂)_n --COOH and

Z is HO--(CH₂)_n --COOH; and

n=1 to 12; and

C represents H, OH, OMe, NH₂, NH--R where R represents C_1-12 alkyl, benzyl, substituted benzyl, (CH₂)_n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H₂ N--(CH₂)_n --COOH, and n=1 to 12.

4. A peptide-lipid conjugate selected from the group consisting of:

(3(S)-X-Asparaginyl)-amino-2(R)-hydroxy-4-phenylbutyl-Pro-C;

(3(S)-X-Asparaginyl)-amino-2(S)-hydroxy-4-phenylbutyl-Pro-C;

(3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-Pro-C;

(3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-Pro-Ile-C;

(3(S)-X-Leucyl-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-Pro-Ile-C;

(3(S)-X-Asparaginyl)-amino-2(R)-hydroxy-4-phenylbutyl-N-1,2,3,4-tetrahydro(R,S)isoquinoline carboxyl-C;

(3(S)-X-Asparaginyl)-amino-2(S)-hydroxy-4-phenylbutyl-N-1,2,3,4-tetrahydro(R,S)isoquinoline carboxyl-C;

(3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-N-1,2,3,4-tetrahydro(R,S)isoquinoline carboxyl-C;

(3(S)-X-Asparaginyl)-amino-2(R,S)-hydroxy-4-phenylbutyl-N-decahydro-3(S)-isoquinoline carboxyl-C;

(3(S)-X-Asparaginyl)-amino-2(R)-hydroxy-4-phenylbutyl-N-decahydro-3(S)-isoquinoline carboxyl-C; and

(3(S)-X-Asparaginyl)-amino-2(S)-hydroxy-4-phenylbutyl-N-decahydro-3(S)-isoquinoline carboxyl-C;

wherein

X represents phosphatidyl-tyrosine;

phosphatidyl-serine;

phosphatidyl-threonine;

phosphatidyl-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;

1-O-acyl-sn-glycero-3-phospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-phospho-O-serine;

1-O-acyl-sn-glycero-3-phospho-O-serine;

1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine;

1-O-acyl-sn-glycero-3-phospho-O-threonine;

1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-diphospho-O-serine;

1-O-acyl-sn-glycero-3-diphospho-O-serine;

1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-diphospho-O-threonine;

1-O-acyl-sn-glycero-3-diphospho-O-threonine;

phosphatidyl ethanolamine-Y;

phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH₂)_n --COOH and

Z is HO--(CH₂)_n --COOH; and

n=1 to 12; and

C represents H, OH, OMe, NH₂, NH--R where R represents C_1-12 alkyl, benzyl, substituted benzyl, (CH₂)_n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H₂ N--(CH₂)_n --COOH, and n=1 to 12.

5. A peptide-lipid conjugate selected from the group consisting of:

4(S)-(X-Alanyl)amino-3(S)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;

4(S)-(X-Alanyl-alanyl)amino-3(S)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;

4(S)-(X-Seryl-alanyl-alanyl)amino-3(S)-hydroxy-5-phenyl-pentanoyl-Val-Val-C

4(S)-(X-Alanyl)amino-3(R)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;

4(S)-(X-Alanyl-alanyl)amino-3(R)-hydroxy-5-phenyl-pentanoyl-Val-Val-C; and

4(S)-(X-Seryl-alanyl-alanyl)amino-3(R)-hydroxy-5-phenyl-pentanoyl-Val-Val-C;

wherein

X represents phosphatidyl-tyrosine;

phosphatidyl-serine;

phosphatidyl-threonine;

phosphatidyl-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;

1-O-acyl-sn-glycero-3-phospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-phospho-O-serine;

1-O-acyl-sn-glycero-3-phospho-O-serine;

1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine;

1-O-acyl-sn-glycero-3-phospho-O-threonine;

1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-diphospho-O-serine;

1-O-acyl-sn-glycero-3-diphospho-O-serine;

1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-diphospho-O-threonine;

1-O-acyl-sn-glycero-3-diphospho-O-threonine;

phosphatidyl ethanolamine-Y;

phosphatidic acid, or phosphatidic acid-Z, wherein Y is HOOC--(CH₂)_n --COOH and

Z is HO--(CH₂)_n --COOH; and

n=1 to 12; and

C represents H, OH, OMe, NH₂, NH--R where R represents C_1-12 alkyl, benzyl, substituted benzyl, (CH₂)_n -phenyl where n=1 to 12, 2-methyl pyridyl, phosphatidyl-tyrosine, phosphatidyl-serine, phosphatidyl-threonine, phosphatidyl-hydroxyproline, 1-O-alkyl-sn-glycero-3-phospho-O-tyrosine, 1-O-acyl-sn-glycero-3-phospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-phospho-O-serine, 1-O-acyl-sn-glycero-3-phospho-O-serine, 1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine, 1-O-acyl-sn-glycero-3-phospho-O-threonine, 1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-acyl-sn-glycero-3-diphospho-O-tyrosine, 1-O-alkyl-sn-glycero-3-diphospho-O-serine, 1-O-acyl-sn-glycero-3-diphospho-O-serine, 1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline, 1-O-alkyl-sn-glycero-3-diphospho-O-threonine, 1-O-acyl-sn-glycero-3-diphospho-O-threonine, phosphatidyl ethanolamine, or phosphatidyl ethanolamine-W, wherein W is H₂ N--(CH₂)_n --COOH, and n=1 to 12.

7. A peptide lipid conjugate of the formula

8. A peptide-lipid conjugate selected from the group consisting of:

X-Val-Phe-Nva-(cyclohexylmethyl(4,4,5,5-tetramethyl-1,3,2-dioxoborlan-2-yl)methylamide;

X-Val-Phe-Nva-(cyclohexylmethyl, dihydroxyboronyl)methylamide;

X-Val-Phe(L-a-Nal)-Nva-(cyclohexylmethyl(4,4,5,5-tetramethyl-1,3,2-dioxoborlan-2-yl)methylamide;

X-Val-Phe(L-a-Nal)-Nva-(cyclohexylmethyl, dihydroxyboronyl)methylamide;

X-Nva(cyclohexylmethyl, dihydroxyboronyl)methylamide; and

X-Val(cyclohexylmethyl, dihydroxyboronyl)methylamide;

wherein;

X represents phosphatidyl-tyrosine;

phosphatidyl-serine;

phosphatidyl-threonine;

phosphatidyl-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-tyrosine;

1-O-acyl-sn-glycero-3-phospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-phospho-O-serine;

1-O-acyl-sn-glycero-3-phospho-O-serine;

1-O-alkyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-phospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-phospho-O-threonine;

1-O-acyl-sn-glycero-3-phospho-O-threonine;

1-O-alkyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-acyl-sn-glycero-3-diphospho-O-tyrosine;

1-O-alkyl-sn-glycero-3-diphospho-O-serine;

1-O-acyl-sn-glycero-3-diphospho-O-serine;

1-O-alkyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-acyl-sn-glycero-3-diphospho-O-hydroxyproline;

1-O-alkyl-sn-glycero-3-diphospho-O-threonine;

1-O-acyl-sn-glycero-3-diphospho-O-threonine;

phosphatidyl ethanolamine-Y;

phosphatidic acid, or phosphatidic acid-Z,

wherein Y is HOOC--(CH₂)_n --COOH;

Z is HO--(CH₂)_n --COOH; and

n=1 to 12.