Design and development of therapeutic drugs for intractable diseases based on molecular recognition of aspartic proteases

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Based on the substrate transition state concept, we designed and synthesized inhibitors of HIV protease that belongs to aspartic protease. We found an innovative hydroxymethylcarbonyl (HMC) isostere as an ideal transition state mimic and succeeded molecular size reduction. These small-sized HIV protease inhibitors are expected as the next generation anti-HIV drugs. HIV protease inhibitors gained epoch-making success but there are many problems left to be solved such as necessity of high dose, side effects, drug resistance.We aimed to develop low-dose anti-HIV drugs with high tissue translocation ability by designing dipeptide-type HIV protease inhibitors containing the ideal transition state mimic, HMC isostere based on the analysis of interaction between the protease and inhibitors. Furthermore, the dipeptide-type small-sized HIV protease inhibitors exhibited effectiveness against drug-resistant virus and different mutation patterns, and thus have a potential to overcome the drug resistance and side effects. Based on the molecular recognition between mutant protease and inhibitors, we designed dipeptide-type HIV protease inhibitors and synthesized their water-soluble prodrugs as well.We applied this useful methodology for design and synthesis of aspartic protease inhibitors to various important proteases such as plasmepsins that play important role in malaria protozoa proliferation, β-secretase that regulates formation of β-peptide and is probably involved in Alzheimer's disease pathology, and HTLV-1 protease that causes adult T-cell leukemia. These inhibitors are expected to be useful in development of therapeutic drugs for intractable diseases.