Abstract

The purpose of this Drug Discovery Program is to develop and screen drugs which will inhibit production and cytopathic effects of the AIDS retrovirus. The proposal combines the capabilities of several laboratory programs of established investigators with proven track record in drug synthesis, analytical pharmacology, experimental chemotherapy and retrovirology. The proposed program consists of four major areas covering drug synthesis, in vitro screening, biological studies and cellular pharmacology. We propose to evaluate a series of nucleoside analogs synthesized at the University of Miami and Birmingham,U.K, natural products isolated and characterized at the University of Arizona and a host of chemicals and culture filterates from UpJohn repository for their anti-viral and anti- viral polymerase activity. Selected drugs which show positive anti-viral and/or anti-viral polymerase activity will be further studied for their transport characteristics, metabolism and cytotoxicity against a panel of human cell lines. Besides these 4 major research areas, we have established 6 core resources to provide laboratory and administrative support to the participants. The overall program will rapidly translate information from all sources into new drug development. Particularly relevant to new drug discovery, the proposed group can evaluate clinical outcome in phase I and II studies in the NIH Drug Evaluation Unit at the University of Miami to validate the in vitro screening techniques. Jointly, the laboratory programs proposed represent an ambitious yet highly pragmatic approach to antiviral chemotherapy for AIDS at the same time as providing the basic research database essential for understanding the mechanisms of action of anti- AIDS' drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI025696-05
Application #
3546752
Study Section
Special Emphasis Panel (SRC (49))
Project Start
1987-09-30
Project End
1992-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
5
Fiscal Year
1991
Total Cost
Indirect Cost

  Institution

Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146

  Publications

Rank, K B; Fan, N; Sharma, S K (1997) A rapid and quantitative assay for inhibition of 3' cleavage activity of HIV-1 integrase. Antiviral Res 36:27-33
Fan, N; Rank, K B; Slade, D E et al. (1996) A drug resistance mutation in the inhibitor binding pocket of human immunodeficiency virus type 1 reverse transcriptase impairs DNA synthesis and RNA degradation. Biochemistry 35:9737-45
Fan, N; Rank, K B; Poppe, S M et al. (1996) Characterization of the p68/p58 heterodimer of human immunodeficiency virus type 2 reverse transcriptase. Biochemistry 35:1911-7
Althaus, I W; Chou, K C; Lemay, R J et al. (1996) The benzylthio-pyrimidine U-31,355, a potent inhibitor of HIV-1 reverse transcriptase. Biochem Pharmacol 51:743-50
Althaus, I W; Franks, K M; Langley, K B et al. (1996) The amphiphilic properties of novenamines determine their activity as inhibitors of HIV-1 RNase H. Experientia 52:329-35
Fan, N; Evans, D B; Rank, K B et al. (1995) Mechanism of resistance to U-90152S and sensitization to L-697,661 by a proline to leucine change at residue 236 of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. FEBS Lett 359:233-8
Pettit, G R; Pettit 3rd, G R; Backhaus, R A et al. (1995) Antineoplastic agents, 294. Variations in the formation of pancratistatin and related isocarbostyrils in Hymenocallis littoralis. J Nat Prod 58:37-43
Fan, N; Rank, K B; Leone, J W et al. (1995) The differential processing of homodimers of reverse transcriptases from human immunodeficiency viruses type 1 and 2 is a consequence of the distinct specificities of the viral proteases. J Biol Chem 270:13573-9
Fan, N; Rank, K B; Evans, D B et al. (1995) Simultaneous mutations at Tyr-181 and Tyr-188 in HIV-1 reverse transcriptase prevents inhibition of RNA-dependent DNA polymerase activity by the bisheteroarylpiperazine (BHAP) U-90152s. FEBS Lett 370:59-62
Evans, D B; Fan, N; Swaney, S M et al. (1994) An active recombinant p15 RNase H domain is functionally distinct from the RNase H domain associated with human immunodeficiency virus type 1 reverse transcriptase. J Biol Chem 269:21741-7

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