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

基于底物过渡态概念，我们设计并合成了属于天冬氨酸蛋白酶的HIV蛋白酶抑制剂。我们发现了一种创新的羟甲基羰基（HMC）等异构体作为理想的过渡态模拟物，并成功地缩小了分子大小。这些小型HIV蛋白酶抑制剂有望成为新一代抗HIV药物。HIV蛋白酶抑制剂取得了划时代的成功，但仍存在大剂量必要性、副作用、耐药等问题。本研究在分析蛋白酶与抑制剂相互作用的基础上，设计了含有理想过渡态模拟物HMC异位体的二肽型HIV蛋白酶抑制剂，旨在开发具有高组织易位能力的低剂量抗HIV药物。此外，二肽型小尺寸HIV蛋白酶抑制剂对耐药病毒和不同的突变模式表现出有效性，从而具有克服耐药和副作用的潜力。基于突变体蛋白酶与抑制剂之间的分子识别，我们设计了二肽型HIV蛋白酶抑制剂，并合成了其水溶性前药。我们将这种有用的方法应用于设计和合成各种重要蛋白酶的天冬氨酸蛋白酶抑制剂，如在疟疾原生动物增殖中起重要作用的plasmepsins，调节β肽形成并可能参与阿尔茨海默病病理的β分泌酶，以及导致成人t细胞白血病的HTLV-1蛋白酶。这些抑制剂有望用于开发治疗顽固性疾病的药物。

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.