Empirical and rational approaches for development of inhibitors of the human immunodeficiency virus--HIV-1.
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.
Department of Pharmacology, Yale University, New Haven, CT 06510.
W
W
Prusoff
T S
TS
Lin
A
A
Pivazyan
A S
AS
Sun
E
E
Birks
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D015195:Drug Design; D006072:Gossypol / Q000031:analogs & derivatives*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis / Q000627:therapeutic use; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D006846:Hydrocarbons, Halogenated; D011480:Protease Inhibitors; D011741:Pyrimidine Nucleosides; D015215:Zidovudine; D006072:Gossypol