Document 0063
 DOCN  M9480063
 TI    Empirical and rational approaches for development of inhibitors of the
       human immunodeficiency virus--HIV-1.
 DT    9410
 AU    Prusoff W; Lin TS; Pivazyan A; Sun AS; Birks E; Department of
       Pharmacology, Yale University, New Haven, CT 06510.
 SO    Pharmacol Ther. 1993 Nov;60(2):315-29. Unique Identifier : AIDSLINE
       MED/94294482
 AB    The human immunodeficiency virus, HIV-1, is generally accepted to be
       responsible for AIDS. It is imperative that all approaches, empirical
       and rational, be taken for development of a drug for therapy of this
       disease. These approaches are discussed, with emphasis on the direction
       being pursued in our laboratory. Empirically, we found
       3'-deoxy-2',3'-didehydrothymidine, a compound first synthesized for
       potential anticancer activity by J. Horwitz in the 1960s, to be a potent
       inhibitor of HIV-1. It is now in Phase II/III clinical trials. We have
       also synthesized several 2,5'-anhydro pyrimidine nucleoside analogs,
       which have interesting chemical and biological properties. We have
       evaluated a natural product, gossypol and synthesized various
       derivatives for anti-HIV-1 activity, but none were appreciably more
       inhibitory than the parent compound. More recently, we have taken the
       rational approach and synthesized a boron-modified tetrapeptide,
       Ac-Thr-Leu-Asn-boro-Phe, which corresponds to the COOH-terminal of the
       Phe-Pro scissle bond of the gag/pol gene polyprotein product. Potent
       inhibition of the HIV-1 encoded protease was observed. These approaches
       and findings will be discussed.
 DE    Amino Acid Sequence  Animal  Antiviral Agents/CHEMISTRY/*CHEMICAL
       SYNTHESIS/THERAPEUTIC USE  Drug Design  Gossypol/*ANALOGS & DERIVATIVES
       Human  Hydrocarbons, Halogenated/CHEMICAL SYNTHESIS/THERAPEUTIC USE  HIV
       Infections/DRUG THERAPY  HIV-1/*DRUG EFFECTS/PHYSIOLOGY  Molecular
       Sequence Data  Protease Inhibitors/CHEMISTRY/*CHEMICAL
       SYNTHESIS/PHARMACOLOGY  Pyrimidine Nucleosides/CHEMISTRY/*CHEMICAL
       SYNTHESIS/THERAPEUTIC  USE  Stereoisomers  Structure-Activity
       Relationship  Support, Non-U.S. Gov't  Support, U.S. Gov't, P.H.S.
       Virus Replication/DRUG EFFECTS  Zidovudine/ANALOGS & DERIVATIVES
       JOURNAL ARTICLE  REVIEW  REVIEW, ACADEMIC

       SOURCE: National Library of Medicine.  NOTICE: This material may be
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