Development of Anti-HIV Compounds

Bodner, Anne J.

Abstract

The long term objective of this proposal is to develop and identify compounds which are effective in treating AIDS and other HIV- related diseases. The studies described in this proposal will aid in the collaborative efforts of this drug discovery group to develop and identify compounds which specifically inhibit HIV enzymes, either reverse transcriptase (RT), endonuclease, or a protease which is thought to be virus specified.
The specific aims of this laboratory will be to: 1) collaborate to better characterize biochemical events following HIV infection in cultured cells, both T-lymphocytes and monocytes/macrophages; 2) furnish immunoaffinity purified RT to the group; 3) immunoaffinity purify the HIV endonuclease, characterize its substrate and develop an endonuclease assay; 4) evaluate anti RT, endonuclease, and protease compounds for cytotoxicity and anti-HIV activity in cultured cells, both T-lymphocytes and monocytes/macrophage; 5) using HIV infected cultured cells, collaborate with other investigators to determine the mode of action of anti-HIV compounds; 6) study selection of virus resistant to anti-HIV compounds; and 7) study the interaction of new compounds with other current or new compounds in inhibiting HIV in cultured cells.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Research Project--Cooperative Agreements (U01)
• Project #: 5U01AI025697-02
• Application #: 3818743
• Support Year: 2
• Fiscal Year: 1988

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