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Novel protease inhibitors markedly adapting to the structural plasticity of HIV-1 protease exert extreme potency with high genetic barrier

Thursday, September 13, 2018 — Poster Session III

12:00 p.m. – 1:30 p.m.
FAES Terrace


  • H Bulut
  • M Aoki
  • H Hayashi
  • H Aoki-Ogata
  • S Hattori
  • AK Ghosh
  • H Mitsuya


Over the last 3 decades, HIV-1 caused a devastating pandemic with ~80 million people infected worldwide and nearly half of them died from the disease, AIDS. Antiretroviral therapy (ART) has been proven to suppress virus replication and significantly elongate the survival of people living with HIV-1. The inhibitors of HIV-1 protease (PIs), an essential enzyme that cleaves gag-pol polyproteins into mature functional proteins, are the key element of ART. Blocking the activity of protease (PR) leaves daughter virions replication-incompetent, enabling the immune system of the hosts restored. However, HIV-1 often acquires resistance to PIs during long-term therapy. Upon comparative analyses of X-ray structures of wild type PR and mutated PR variants such as PRs of HIVDRVRP30 and HIVDRVRP51 (in vitro selected with darunavir, DRV, over 30 or 51 weeks, respectively), we identified multiple critical residues (F33, M45, R20, and D35) that induce the structural deformation in PR structure. In order to overcome the reduced affinity as a result of structural plasticity of PR, we systematically modified the chemical moieties around the scaffold of DRV and synthesized various novel PIs. In particular, we introduced a P2’ cyclopropyl-amino-benzothiazole moiety (Cp-Abt) or P2’ isopropyl-amino-benzoxazole (Ip-Abo) at the S2’ sub-pocket and a benzene ring located in the S1 sub-pocket with fluorine atoms at meta or para positions, and examined their anti-HIV-1 potency and cell permeability.

Category: Structural Biology