Design of resistance-surmountable HIV protease inhibitors based on molecular recognition analysis of mutant protease

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Introduction of HIV protease inhibitors with new action mechanism as anti-HIV drugs provided a new development in the combination therapy of AIDS. However, there are many problems to be solved such as dose, economics, side effects, resistance, transport to central nervous system.In order to overcome these problems, we designed and synthesized small-sized HIV protease inhibitors containing hydroxymethylcarbonyl (HMC) isostere, an ideal transition state mimic, based on the data obtained from molecular recognition analysis. Inhibitors of small size and high potency are advantageous in terms of cost and resistance induction as well because molecular recognition studies showed that these inhibitors interacts with the enzyme at fewer sites. Furthermore, hybrid-type anti-HIV drugs conjugated with reverse transcriptase inhibitors may exhibit better cell membrane permeability, and synergistic effect leading to practical resistance-surmountable HIV protease inhibitors of third generation. As a result, we obtained a highly potent 'double-drug' consisting of dipeptide, KNI-727 conjugated with a reverse transcriptase inhibitor, AZT through a spontaneously cleavable linker. We also synthesized water soluble prodrugs using intramolecular acyl migration reaction and succeeded to control the releasing time of the active molecules from the prodrugs.In the new design aspect, we synthesized inhibitors containing L-tetrahydrofuranylglicine to show that the inhibitors interacts favorably with the enzyme at the S2 site. Pseudo-symmetric inhibitors containing hydroxymethylcarbonyl hydrazide at P1-P1' position exhibited high HIV protease inhibitory activity.Alternatively, dipeptide inhibitors, KNI-727 and KNI-764 selectively inhibited plasmepsin II which plays important role in the proliferation of malaria parasite and belongs to the aspartic protease family. Thus, we showed that our inhibitor design methodology is widely applicable to inhibit aspartic proteases from various origins.