US 5,512,548 AGranted

CETP inhibitor polypeptide, antibodies against the synthetic polypeptide and prophylactic and therapeutic anti-atherosclerosis treatments

AssigneeSouthwest Foundation for Biomedical Research

InventorsRampratap Kushwaha, Kathleen Born, Henry C. McGill, Jr., Patrick Kanda, Raymond G. Dunham

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Abstract

A polypeptide and analogues thereof inhibit cholesteryl ester transfer protein (CETP). An anti-atherosclerosis composition comprises an anti-atherosclerosis effective amount of the polypeptide and a pharmaceutically-acceptable carrier. An anti-atherosclerosis kit comprises in separate sterile containers at least one unit of the composition containing the polypeptide, one syringe and one needle. An antibody has specificity for the polypeptide of the invention, the baboon CETP 4kD polypeptide inhibitor, the 1-36 amino acid N-terminal fragment of apo C-I, modified apo A-I (MW:31kD) or modified apo E (MW:41kD). A method of preventing atherosclerosis in a mammal being predisposed to that condition comprises administering to the mammal a prophylactically effective amount of the polypeptide of the invention, and a method of treating a mammal afflicted with atherosclerosis comprises the administration of a therapeutically affective amount of the polypeptide disclosed herein.

Claims10

Dependent claims

A method of preventing atherosclerosis in a mammal being predisposed to that condition, comprising a cholesteryl ester transfer protein inhibitory polypeptide of sequence

Asp-Val-Ser-Ser-Ala-Leu-Asp-Lys-Leu-Lys-Glu-Phe-Gly-Asn-Thr-Leu-Glu-Asp-Lys -Ala-Trp-Glu-Val-Ile-Asn-Arg-Ile-Lys-Gln-Ser-Glu-Phe-Pro-Ala-Lys-Thr
(SEQ. ID. NO:
1)
wherein the cholesteryl ester transfer protein inhibitory polypeptide has at least one substitute amino acid or amino bond;
the substitute amino acid for Asp being selected from the group consisting of Glu, C.sub..alpha. -methylVal;
the substitute amino acid for Val being selected from the group consisting of isoVal, nor Val, Leu, and C.sub..alpha. -methylVal;
the substitute amino acid for Ala being selected from the group consisting of Gly, .beta.-Ala, C.sub..alpha. -methylAla, and 2-amino butyric acid;
the substitute amino acid for Leu being selected from the group consisting of norLeu, isoLeu, and C.sub..alpha. -methylLeu;
the substitute ammo acid for Lys being selected from the group consisting of ornithine, Arg, citrulline and C.sub..alpha. -methylLys;
the substitute ammo acid for Gly being selected from the group consisting of Ala and 2-amino isobutyric acid;
the substitute ammo acid for Asn being selected from the group consisting of Gln, citrulline, and C.sub..alpha. -methyl Asn;
the substitute ammo acid for Trp being selected from the group consisting of p-benzoylPhe, Arg and C.sub..alpha. -methyl Trp;
the substitute amino acid for Glu being selected from the group consisting of 2-amino adipic acid, Asp, and C.sub..alpha. -methylGlu;
the substitute amino acid for Ile being selected from the group consisting of Leu, norLeu, and C.sub..alpha. -methylLeu;
the substitute amino acid for Arg being selected from the group consisting of Lys, homoArg, citrulline and C.sub..alpha. -methylArg;
the substitute amino acid for Gln being selected from the group consisting of Ash, citrulline, and C.sub..alpha. -methylGln;
the substitute amino acid for Phe being selected from the group consisting of 2-amino-4-phenylbutyric acid, Leu and C.sub..alpha. -methylPhe;
the substitute amino acid for Thr being selected from the group consisting of Ser, Met and C.sub..alpha. -methylThr;
the substitute amino acid for Set being selected from the group consisting of Thr and C.sub..alpha. -methylSer;
the substitute amino acid for Pro being selected from the group consisting of 3,4-dehydroPro, Ser and C.sub..alpha. -methylPro;
and
the substitute amino acid bond being selected from the group consisting of thioether, alkyl, alkyl amino, and combinations of thioether, alkyl and alkyl amino bonds

19 more elements

A method of treating a mammal afflicted with atherosclerosis comprising administering to the mammal a therapeutically effective amount of a cholesteryl ester transfer protein inhibitory polypeptide of sequence

Asp-Val-Ser-Ser-Ala-Leu-Asp-Lys-Leu-Lys-Glu-Phe-Gly-Asn-Thr-Leu-Glu-Asp-Lys -Ala-Trp-Glu-Val-Ile-Asn-Arg-Ile-Lys-Gln-Ser-Glu-Phe-Pro-Ala-Lys-Thr
(SEQ. ID. NO:
1)
wherein the cholesteryl ester transfer protein inhibitory polypeptide has at least one substitute amino acid or amino bond;
the substitute amino acid for Asp being selected from the group consisting of Glu, C.sub..alpha. -methylVal;
the substitute amino acid for Val being selected from the group consisting of isoVal, nor Val, Leu, and C.sub..alpha. -methylVal;
the substitute amino acid for Ala being selected from the group consisting of Gly, .beta.-Ala, C.sub..alpha. -methylAla, and 2-amino butyric acid;
the substitute amino acide for Leu being selected from the group consisting of norLeu, isoLeu, and C.sub..alpha. -methylLeu;
the substitute amino acid for Lys being selected from the group consisting of ornithine, Arg, citrulline and C.sub..alpha. -methylLys;
the substitute amino acid for Gly being selected from the group consisting of Ala and 2-amino isobutyric acid;
the substitute amino acid for Asn being selected from the group consisting of Gln, citrulline, and C.sub..alpha. -methyl Asn;
the substitute amino acid for Trp being selected from the group consisting of p-benzoyl Phe, Arg and C.sub..alpha. -methyl Trp;
the substitute amino acid for Glu being selected from the group consisting of 2-amino adipic acid, Asp, and C.sub..alpha. -methylGlu;
the substitute amino acid for He being selected from the group consisting of Leu, norLeu, and C.sub..alpha. -methylLeu;
the substitute amino acid for Arg being selected from the group consisting of Lys, homoArg, citrulline and C.sub..alpha. -methylArg;
the substitute amino acid for Gln being selected from the group consisting of Ash, citrulline, and C.sub..alpha. -methylGln;
the substitute amino acid for Phe being selected from the group consisting of 2-amino-4-phenyl butyric acid, Leu and C.sub..alpha. -methylPhe;
the substitute amino acid for Thr being selected from the group consisting of Ser, Met and C.sub..alpha. -methylThr;
the substitute amino acid for Ser being selected from the group consisting of Thr and C.sub..alpha. -methylSer;
the substitute amino acid for Pro being selected from the group consisting of 3,4-dehydroPro, Set and C.sub..alpha. -methylPro;
and
the substitute amino acid bond being selected from the group consisting of thioether, alkyl, alkyl amino, and combinations of thioether, alkyl and alkyl amino bonds. g1 administering to the mammal a prophylactically effective amount of

19 more elements

Dependencies are inferred from the claim text.