Inhibition of HIV-1 protease in infected T-lymphocytes by synthetic peptide analogues.
The gag and pol genes of the human immunodeficiency virus type 1 (HIV-1) (ref. 1) are translated as two polyproteins, Pr55gag and Pr160gag-pol (refs 2-6), which are subsequently cleaved by the action of a virus-encoded protease into the four structural gag proteins of the virion core (p17, p24, p7 and p6) and the pol-encoded enzymes essential for retrovirus replication (protease, reverse transcriptase, ribonuclease H, and endonuclease). Mutational inactivation of the proteases of HIV-1 and other retroviruses results in immature, non-infectious virions, indicating that exogenous inhibition of the protease may represent an attractive approach to anti-AIDS therapy. Here we demonstrate that synthetic peptide analogues, which are potent inhibitors of purified HIV-1 protease, inhibit the processing of the viral polyproteins in cultures of HIV-1-infected T lymphocytes and attenuate viral infectivity.
Department of Medicinal Chemistry, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406.
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Meek
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Lambert
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Dreyer
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Carr
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Tomaszek
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Moore
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Strickler
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Hyland
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D000595:Amino Acid Sequence; D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism*; D015685:Fusion Proteins, gag-pol / Q000378:metabolism; D015683:Gene Products, gag / Q000378:metabolism; D016333:HIV Protease; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000382:microbiology; D014779:Virus Replication / Q000187:drug effects
D015685:Fusion Proteins, gag-pol; D015683:Gene Products, gag; D009842:Oligopeptides; D011480:Protease Inhibitors; D012194:RNA-Directed DNA Polymerase; D010450:Endopeptidases; D016333:HIV Protease