Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance

Arun K. Ghosh*, Perali Ramu Sridhar, Sofiya Leshchenko, Azhar K. Hussain, Jianfeng Li, Andrey Yu Kovalevsky, D. Eric Walters, Joseph E. Wedekind, Valerie Grum-Tokars, Debananda Das, Yasuhiro Koh, Kenji Maeda, Hiroyuki Gatanaga, Irene T. Weber, Hiroaki Mitsuya

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b] furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino)sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[e]furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 Å resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.

Original languageEnglish (US)
Pages (from-to)5252-5261
Number of pages10
JournalJournal of Medicinal Chemistry
Issue number17
StatePublished - Aug 24 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


Dive into the research topics of 'Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance'. Together they form a unique fingerprint.

Cite this