Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands

Arun K. Ghosh, Cuthbert D. Martyr, Luke A. Kassekert, Prasanth R. Nyalapatla, Melinda Steffey, Johnson Agniswamy, Yuan Fang Wang, Irene T. Weber, Masayuki Amano, Hiroaki Mitsuya

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. The majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.

Original languageEnglish (US)
Pages (from-to)11607-11621
Number of pages15
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number48
DOIs
StatePublished - Oct 14 2015

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© The Royal Society of Chemistry.

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