Development of Anti-AIDS Agents

Cheng, Yung-Chi

Abstract

The overall goal of this proposal is (1) to develop selective anti- human immunodeficiency virus (HIV) agents by taking advantage of unique properties of HIV pol gene products, reverse transcriptase (RT), protease and endonuclease (EN), (2) to study the metabolism and mechanism of action of antiviral agents, (3) to study the mechanism and development of drug resistance in order to get insight into using those agents effectively.
The specific aims i nclude: a) the study of biochemical events in cells infected with HIV, b) a comparison of virus specified and human enzymes, c) designing and synthesizing compounds which could interact with the virus specified enzymes, and d) study of those compounds which have potential anti-HIV activity with respect to their biological activity, metabolism and mechanism of action. Some of these projects will be done in collaboration with other investigators involved with this proposed program, but the study of RT as one of the potential enzyme targets and the study of the biochemical pharmacology of potential anti-HIV drugs are the major focus of this laboratory.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Research Project--Cooperative Agreements (U01)
• Project #: 1U01AI025697-01
• Application #: 3822537
• Support Year: 1
• Fiscal Year: 1987

Institution

• Name: George Washington University
• City: Washington
• State: DC
• Country: United States
• Zip Code: 20052

Publications

Ju, Jingyue; McKenna, Charles E (2002) Synthesis of oligodeoxyribonucleoside phosphorothioates using Lawesson's reagent for the sulfur transfer step. Bioorg Med Chem Lett 12:1643-5

Bau, R; Pham, P T; Duncan, G D et al. (1995) Absolute configuration of (+)-[fluoro(hydroxyphenylphosphinyl)methyl]-phosphonic acid, a specific inhibitor of Na(+)-gradient-dependent Na(+)-phosphate cotransport across renal brush border membrane, by X-ray crystallographic analysis of its (-)-quinine s J Med Chem 38:1575-8

Peng, Z Y; Mansour, J M; Araujo, F et al. (1995) Some phosphonic acid analogs as inhibitors of pyrophosphate-dependent phosphofructokinase, a novel target in Toxoplasma gondii. Biochem Pharmacol 49:105-13

Mellors, J W; Im, G J; Tramontano, E et al. (1993) A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to (+)-(5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5, 1- jk][1,4]benzodiazepin-2(1H)-thione (TIBO R82150). Mol Pharmacol 43:11-6

McKenna, C E; Pham, P T; Rassier, M E et al. (1992) Alpha-halo [(phenylphosphinyl)methyl]phosphonates as specific inhibitors of Na(+)-gradient-dependent Na(+)-phosphate cotransport across renal brush border membrane. J Med Chem 35:4885-92

Mellors, J W; Dutschman, G E; Im, G J et al. (1992) In vitro selection and molecular characterization of human immunodeficiency virus-1 resistant to non-nucleoside inhibitors of reverse transcriptase. Mol Pharmacol 41:446-51

Chen, K; Shi, Q A; Fujioka, T et al. (1992) Anti-AIDS agents, 4. Tripterifordin, a novel anti-HIV principle from Tripterygium wilfordii: isolation and structural elucidation. J Nat Prod 55:88-92

Pettit, S C; Simsic, J; Loeb, D D et al. (1991) Analysis of retroviral protease cleavage sites reveals two types of cleavage sites and the structural requirements of the P1 amino acid. J Biol Chem 266:14539-47

Radzicka, A; Wolfenden, R (1991) Analogues of intermediates in the action of pig kidney prolidase. Biochemistry 30:4160-4

Tatematsu, H; Kilkuskie, R E; Corrigan, A J et al. (1991) Anti-AIDS agents, 3. Inhibitory effects of colchicine derivatives on HIV replication in H9 lymphocyte cells. J Nat Prod 54:632-7