Protease inhibitors exerting potent activity against wild type and multi-drug resistant HIV-1 variants without boosters.

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K19577
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pathology, Infection/Immunology, and related fields
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: Mitsuya Hiroaki 国立研究開発法人国立国際医療研究センター, その他部局等, 研究所長 (20136724)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Keywords: ウイルス / HIV-1 / プロテアーゼ阻害剤 / CYP3A4 / 薬物動態

Outline of Final Research Achievements

We demonstrated that multiple novel PIs, which contain the tetrahydropyrano-tetrahydrofuran moiety (Tp-THF) with a C5-alkylamino group as a P2-ligand, displayed increased resistance to the metabolic activity of CYP enzymes. In particular, GRL-079-13A and GRL-015-16A, which contain P2-C5-alkylamino-modified Tp-THF and P2’-cyclopropyl-amino-benzothiazole (P2’-Cp-Abt), displayed increased CYP resistance as RTV and COBI did. We also determined the relationship between the chemical structures of PIs containing Tp-THF and the increase of intracellular TG amount in HepG2 cells. We found that P2’-Cp-Abt and P1-di-meta-fluorine modification increases intracellular TG levels but amine and methylamino modifications at the C5-position of Tp-THF do not affect adversely TG levels in HepG2 cells. These data would be useful to design novel PIs, which simplify the drug regimen by removing RTV or COBI from cART, thereby decreasing adverse effects in lipid metabolisms and drug-drug interactions.

Free Research Field

感染症内科学、レトロウイルス感染症、抗ウイルス治療薬開発

Academic Significance and Societal Importance of the Research Achievements

ブースターを必要とせずQW又はQMでの投与で野生株及び多剤耐性HIV-1株の両方に高い阻害効果を発揮する抗 HIV-1剤を同定・開発するという本研究の試みはドラッグデザインの領域でも極めて先進的・挑戦的である。本研究で得られたCYP耐性と化合物の構造の相関関係はそのような新規抗HIV-1剤開発の基盤を成すものであり学術的・社会的意義は計り知れない。また、本研究成果は、ART の投薬方法の変革と感染患者のQOLの向上に必須であり、新たなHIV-1治療法の開拓に資する重要な成果である。