Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants

Arun K. Ghosh, Kalapala Venkateswara Rao, Prasanth R. Nyalapatla, Heather L. Osswald, Cuthbert D. Martyr, Manabu Aoki, Hironori Hayashi, Johnson Agniswamy, Yuan Fang Wang, Haydar Bulut, Debananda Das, Irene T. Weber, Hiroaki Mitsuya

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2′ ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

Original languageEnglish
Pages (from-to)4267-4278
Number of pages12
JournalJournal of Medicinal Chemistry
Volume60
Issue number10
DOIs
Publication statusPublished - 2017 May 25

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Ghosh, A. K., Rao, K. V., Nyalapatla, P. R., Osswald, H. L., Martyr, C. D., Aoki, M., Hayashi, H., Agniswamy, J., Wang, Y. F., Bulut, H., Das, D., Weber, I. T., & Mitsuya, H. (2017). Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. Journal of Medicinal Chemistry, 60(10), 4267-4278. https://doi.org/10.1021/acs.jmedchem.7b00172