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

基于突变蛋白酶分子识别分析的可克服耐药性的HIV蛋白酶抑制剂的设计

基本信息

批准号：
12470508
负责人：
KISO Yoshiaki
金额：
$ 7.04万
依托单位：
Kyoto Pharmaceutical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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.

具有新作用机制的HIV蛋白水解酶抑制剂作为抗HIV药物的引入，为艾滋病的综合治疗提供了新的发展。为了克服这些问题，我们在分子识别分析数据的基础上，设计并合成了含有理想过渡态模拟物羟甲基羰基(HMC)异构酶的小分子HIV蛋白水解酶抑制剂。小尺寸和高效力的抑制剂在成本和抗性诱导方面也具有优势，因为分子识别研究表明这些抑制剂与酶相互作用的位点较少。此外，与逆转录酶抑制剂结合的杂交型抗HIV药物可能会表现出更好的细胞膜通透性，并具有协同效应，从而产生实用的第三代可克服耐药性的HIV蛋白酶抑制剂。因此，我们通过一个可自发切割的连接子，获得了一种由二肽组成的高度有效的‘双药’，KNI-727与逆转录酶抑制剂AZT偶联。在新的设计方面，我们合成了含有L-四氢呋喃甘氨酸的抑制剂，表明这些抑制剂与S2位的酶有良好的相互作用。另外，二肽抑制剂KNI-727和KNI-764选择性地抑制纤溶酶II，纤溶酶II是天冬氨酸蛋白水解酶家族的重要成员。因此，我们表明我们的抑制剂设计方法广泛适用于抑制不同来源的天冬氨酸蛋白酶。