Method for identifying HIV-1 protease inhibitors with reduced metabolic affects

• US 7,598,029 B2
• Filed: 12/22/2008
• Issued: 10/06/2009
• Est. Priority Date: 06/30/2006
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Ranade, Koustubh, Geese, William J.
• Primary Examiner(s): Nickol; Gary B
• Assistant Examiner(s): KINSEY WHITE, NICOLE ERIN
• Application Number:
  US12/317,322
• Publication Number:
  US 20090117535A1
• Time in Patent Office: 288 Days
• Field of Search: None
• US Class Current: 435/4
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C12Q 1/6827 for detection of mutation or polymorphism

Abstract

The invention provides a novel in vitro method for identifying HIV-1 protease inhibitors with reduced potential for inducing metabolic abnormalities. The invention further provides diagnostic methods for identifying patients who may be at risk of developing metabolic abnormalities subsequent to the administration of an HIV-1 protease inhibitor. The invention also provides novel polynucleotides associated with the incidence of HIV-1 protease inhibitor induced metabolic abnormalities. The invention also provides polynucleotide fragments corresponding to the genomic and/or coding regions of these polynucleotides which comprise at least one polymorphic locus per fragment. Allele-specific primers and probes which hybridize to these regions, and/or which comprise at least one polymorphic locus are also provided. The polynucleotides, primers, and probes of the present invention are useful in phenotype correlations, medicine, and genetic analysis. The invention further relates to diagnostic methods for using these novel polynucleotides in the diagnosis, treatment, and/or prevention of HIV-1 protease inhibitor induced metabolic abnormalities.

Claims

1. A method of identifying a HIV-1 protease inhibitor compound having a decreased likelihood of inducing HIV-1 protease inhibitor-dependent metabolic abnormalities in a mammal comprising the step of:

a) incubating resistin, with a cathepsin, in the presence of a test compound; and

b) measuring the level of proteolyzed resistin;

wherein a diminished level or absence of proteolyzed resistin by the test compound relative to a control is indicative of a decreased probability said compound will cause HIV-1 protease inhibitor-dependent metabolic abnormalities in said mammal.

2. The method according to claim 1, wherein said cathepsin is cathepsin D.

3. The method according to claim 1, wherein said cathepsin is cathepsin E.

4. The method according to claim 1, wherein said resistin is denatured.

5. The method according to claim 4, wherein said resistin is denatured by alkylation.

6. The method according to claim 1, wherein the cysteine residues of said resistin are reduced.

7. The method according to claim 1, wherein said resistin is denatured by alkylation and the cysteine residues of said resistin are reduced.

8. The method according to claim 1, wherein said cathepsin is activated prior to incubation with resistin.