Design and synthesis of a covalently linked HIV-1 protease dimer analog and peptidomimetic inhibitors

The HN-I 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 HN-I 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. 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-I 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-MN drugs.