Development of Novel HIV-1 Protease Dimerization Inhibitors Using Crystal Structure, Thermal Stability and Mass Spectrum Analyses

2015 Fiscal Year Final Research Report

• Project/Area Number: 15K15382
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Infectious disease medicine
• Research Institution: Kumamoto University
• Principal Investigator: Mitsuya Hiroaki 熊本大学, 大学院生命科学研究部, 教授 (20136724)
• Project Period (FY): 2015-04-01 – 2016-03-31
• Keywords: AIDS/HIV-1 / 二量体化阻害剤 / 結晶構造解析 / 熱安定性 / 質量分析

Outline of Final Research Achievements

The purpose of this project was the development of novel HIV-1 protease dimerization inhibitors (PDIs), which were potent against both wild type HIV-1 (HIV-1WT) and multiple drug-resistant HIV-1 variants (HIV-1MDRs). During the study period, we obtained two important results. (i) Using the crystal structural analysis, we identified key functional groups of novel protease inhibitors (GRL-015, -085, and -097). The functional groups in such protease inhibitors interacted with the flap region of HIV-1 protease and enabled such novel inhibitors to block the replication of HIV-1MDRs. (ii) Using electrospray ionization mass spectrometer (ESI-MS), we demonstrated the mechanisms of the most potent PDI termed as KU-241. KU-241 inhibited PR dimerization by binding PR monomer in the same way as darunavir, which was approved by FDA in 2006. The present results should shed light on designing further novel PDIs, which would inhibit both HIV-1WT and HIV-1MDRs.

Free Research Field

医学、ウイルス学、感染症学、創薬化学