Peptide substrates and inhibitors of the HIV-1 protease |
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| Authors: | M L Moore W M Bryan S A Fakhoury V W Magaard W F Huffman B D Dayton T D Meek L Hyland G B Dreyer B W Metcalf |
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| Institution: | Department of Peptide Chemistry, Smith Kline & French Laboratories, King of Prussia, PA 19406. |
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| Abstract: | Oligopeptides containing the consensus retroviral protease cleavage sequence Ser/Thr-X-Y-Tyr/Phe-Pro are substrates for purified recombinant HIV-1 protease with Km's in the millimolar range. The minimum sequence containing the consensus pentapeptide which serves as a good substrate is a heptapeptide spanning the P4-P3' residues. Substitution of reduced Phe-Pro or Tyr-Pro dipeptide isosteres or the statine analog 3-hydroxy-4-amino-5-phenylpentanoic acid for the scissile dipeptide afforded inhibitors of HIV-1 protease with Ki values in the micromolar range, three orders of magnitude better in affinity than the corresponding substrates. Inhibitors of HIV-1 protease may provide a novel and potentially useful therapeutic approach to the treatment of acquired immune deficiency syndrome (AIDS). |
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