Uses of cyclic peptides for treating and preventing atherosclerosis
AssigneeThe Scripps Research Institute
InventorsM. Reza Ghadiri, Luke J. Leman, Yannan Zhao, Bruce E. Maryanoff
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Abstract
The present invention provides cyclic compounds that are useful in preventing or treating atherosclerosis or related disorders. The invention also provides therapeutic methods for treating or preventing various diseases or disorders associated with or mediated by atherosclerosis. Further provided in the invention are methods of screening for anti-atherosclerotic cyclic peptides with improved properties.
Claims7
A method for treating or preventing atherosclerosis or a disorder associated with or mediated by atherosclerosis, comprising administering to a subject afflicted with or at risk of developing atherosclerosis, or a disorder associated with or mediated by atherosclerosis, a therapeutically effective amount of a pharmaceutical composition comprising a cyclic peptide consisting of about eight alternating D- and L-amino acid residues or analogs along its entire sequence, wherein the cyclic peptide compound has a sequence formula of c[B-J-U1-X-U2-Z], wherein B consists of DTrp-Leu-DTrp or DTyr-Leu-DTyr;
- J is Lys, Arg, or Ser;
- U1 and U2 are each independently a DAsp, DGlu or DSer residue;
- X is Asn or Gln;
- and Z is Lys, Arg, Orn (ornithine) or diaminobutyric acid.
A method for treating or preventing atherosclerosis or a disorder associated with or mediated by atherosclerosis, comprising administering to a subject afflicted with or at risk of developing atherosclerosis, or a disorder associated with or mediated by atherosclerosis, a therapeutically effective amount of a pharmaceutical composition comprising a cyclic peptide having alternating D- and L-residues along its partial or entire sequence, wherein the cyclic peptide is selected from the group consisting of c[wLwReQeR] (SEQ ID NO:1), c[wLwKdQeK] (SEQ ID NO:2), c[wLwRdQeK] (SEQ ID NO:3), c[wLwSeQsO] (SEQ ID NO:4), c[fWwYqHhQ] (SEQ ID NO:5), c[LwLwLrKe] (SEQ ID NO:6), c[wLwZeQeK] (SEQ ID NO:7), c[wLwKdNdK] (SEQ ID NO:8), c[wLwRdNdK] (SEQ ID NO:9), c[wLwKdQdK] (SEQ ID NO:10), c[wLwKeNeK] (SEQ ID NO:11), c[wLwHeNeK] (SEQ ID NO:12), c[wLwOeQeO] (SEQ ID NO:13), c[wLMewSeQMesO] (SEQ ID NO:14), and c[wLwOeNeO] (SEQ ID NO:19), c[w(Aoc)wSeQsO] (SEQ ID NO:22), c[wLwReNeO] (SEQ ID NO:23), c[wLwHeQeH] (SEQ ID NO:24), c[yWyKsHaE] (SEQ ID NO:25), c[wL1wKdDk] (SEQ ID NO:26), c[w(Nal)wReQeR] (SEQ ID NO:28), c[w(Hml)wReQeR] (SEQ ID NO:29), c[wLwSeQhK] (SEQ ID NO:40), c[(Me)wLwR(Me)eQeR] (SEQ ID NO:46), c[WIWwkhkh] (SEQ ID NO:47), c[wFyYhOrS] (SEQ ID NO:48), c[(PA)wL1HsKk] (SEQ ID NO:49), c[WIWrEqEr] (SEQ ID NO:50), c[fWwYtRhS (SEQ ID NO:51)], c[wFfYrHhS] (SEQ ID NO:52), and c[wLwKhShK] (SEQ ID NO:53), and conservatively substituted sequences thereof.
A method for treating or preventing atherosclerosis or a disorder associated with or mediated by atherosclerosis, comprising administering to a subject afflicted with or at risk of developing atherosclerosis, or a disorder associated with or mediated by atherosclerosis, a therapeutically effective amount of a pharmaceutical composition comprising a cyclic peptide, wherein the cyclic peptide compound has a sequence formula of c[wLw-J-u1-X-u2-Z] and comprises about 8 alternating D- and L-form of amino acid residues or amino acid analogs, wherein “wLw” denotes a tripeptide segment consisting of DTrp-Leu-DTrp;
- J is serine or a positively charged amino acid residue or analog;
- u1 and u2 are each independently a DAsp, DGlu or DSer residue;
- X is Asn residue or Gln residue;
- and Z is a positively charged amino acid residue or analog.
Dependencies are inferred from the claim text.