Design and Synthesis of a Covalently Linked HIV-1 Protease Dimer Analog and Peptidomimetic Inhibitors.

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  • Kiso Yoshiaki
    Department of Medicinal Chemistry, Kyoto Pharmaceutical University

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  • Design and Synthesis of a Covalently Li

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The HIV-1 protease analogs were synthesized by the solid-phase method and the dimer analog covalently linked by a disulfide bridge was constructed using the thioether chemical ligation method. The HIV-1 protease analogs effectively cleaved the Tyr-Phe-type substrate, but had weak affinity to the Tyr-Pro-type substrate. Consequently, the molecular recognition of the analogs differs from the wild-type enzyme.<BR>Based on the substrate transition-state mimetic concept, allophenylnorstatine-containing HIV protease inhibitors were designed and synthesized. Among them, a dipeptide-based HIV protease inhibitor, KNI-764, exhibited potent antiviral activities, low cytotoxicity and good pharmacokinetic properties. Also, KNI-764 showed strong inhibition against both wild-type HIV-1 protease and synthetic HIV protease analogs, whereas saquinavir, ritonavir, and indinavir weakly inhibited the synthetic protease analogs. This study suggests that the small-sized dipeptide HIV protease inhibitor, KNI-764, is a good candidate for anti-HIV drugs.

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