Study on strategy for AIDS drugs against mutant viruses

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Based on the substrate transition state concept of HIV protease, we have designed and synthesized HIV protease inhibitors containing hydroxymethylcarbony (HMC) isostere. Among them, a tripeptide derivative KNI-272 exhibited high selectivity, potent HIV protease inhibition, and high in vivo antiviral activity. NMR and molecular modeling studies showed that the HMC group interacts favorable with HIV protease active site and that the HMC isostere is an ideal transition state mimic.The HIV protease inhibitors currently used for therapeutics need high dose and thus cause various side effects. Furthermore, HIV protease inhibitors induce mutation in the amino acid sequence of HIV-1 protease and decreased sensitivity, although HIV protease inhibitors have been considered as low mutation inducer because they attack the enzyme active center.Therefore, we started the design and synthesis of low molecular weight HIV protease inhibitors. The small and potent inhibitors may be favorable in terms of the cost, resistance induction, pharmacokinetics and administration dose.Taking into consideration of these factors, based on the molecular recognition between the enzyme and inhibitors, we designed small-sized highly-potent HIV protease inhibitors containing HMC isostere, and found the possibility to overcome the resistance and side effects. Furthermore, we synthesized prodrug-type conjugates of dipeptide HIV protease inhibitors with a reverse transcriptase inhibitors. We found that these new type of anti-HIV drugs showed excellent cell membrane permeability and synergistic effect, and proposed "Double-Drug" concept.