Abstract

A multi-institutional group seeks to renew funding of a very successful ongoing collaboration that has already identified a clinical candidate for treating HIV-1 infection, i.e., U-87201E, a nonnucleoside inhibitor of the HIV-1 reverse transcriptase (RT). This proposal contains 4 projects that represent an integrated, rational plan to identify, evaluate, and optimize novel inhibitors of HIV replication. Four of the project at Upjohn Laboratories will principally seek to identify and optimize the antiviral and pharmaceutical properties of inhibitors of the essential ribonuclease H (RNase H) activity of the HIV RT. These projects will integrate with one another and use a """"""""Structure- Driven Drug Design Paradigm"""""""" to develop lead inhibitors into drug candidates. Studies investigating RT subunit interaction as it relates to the control of reverse transcription will be performed. Work on new classes of RT inhibitors already identified in the Upjohn chemical inventory will be evaluated for novel mechanisms of inhibiting the HIV RT. Together these projects represent a group of research talents not attainable at any single institution. The experience of this group and their documented productivity in the AIDS research area, insure this program will continue to be successful.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI025696-07
Application #
3546753
Study Section
Special Emphasis Panel (SRC (58))
Project Start
1987-09-30
Project End
1996-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
7
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
Pharmacia and Upjohn, Inc.
Department
Type
DUNS #
City
Kalamazoo
State
MI
Country
United States
Zip Code
49001

  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; 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; 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; 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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