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Title: Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance

Abstract

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[b]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 Angstroms 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.

Authors:
; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
914305
Report Number(s):
BNL-78873-2007-JA
Journal ID: ISSN 0022-2623; JMCMAR; TRN: US200809%%162
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Med. Chem.; Journal Volume: 49; Journal Issue: 17
Country of Publication:
United States
Language:
English
Subject:
08 HYDROGEN; 36 MATERIALS SCIENCE; AIDS VIRUS; BONDING; CHOLINESTERASE; CRYSTAL STRUCTURE; CYCLIZATION; DESIGN; ENZYMES; HYDROGEN; RADICALS; RESOLUTION; STRAINS; SYNTHESIS; URETHANE; national synchrotron light source

Citation Formats

Ghosh,A., Sridhar, P., Leshchenko, S., Hussain, A., Li, J., Kovalevsky, A., Walters, D., Wedelind, J., Grum-Tokars, V., and et al. Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance. United States: N. p., 2006. Web. doi:10.1021/jm060561m.
Ghosh,A., Sridhar, P., Leshchenko, S., Hussain, A., Li, J., Kovalevsky, A., Walters, D., Wedelind, J., Grum-Tokars, V., & et al. Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance. United States. doi:10.1021/jm060561m.
Ghosh,A., Sridhar, P., Leshchenko, S., Hussain, A., Li, J., Kovalevsky, A., Walters, D., Wedelind, J., Grum-Tokars, V., and et al. Sun . "Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance". United States. doi:10.1021/jm060561m.
@article{osti_914305,
title = {Structure-Based Design of Novel HIV-1 Protease Inhibitors to Combat Drug Resistance},
author = {Ghosh,A. and Sridhar, P. and Leshchenko, S. and Hussain, A. and Li, J. and Kovalevsky, A. and Walters, D. and Wedelind, J. and Grum-Tokars, V. and et al.},
abstractNote = {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[b]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 Angstroms 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.},
doi = {10.1021/jm060561m},
journal = {J. Med. Chem.},
number = 17,
volume = 49,
place = {United States},
year = {Sun Jan 01 00:00:00 EST 2006},
month = {Sun Jan 01 00:00:00 EST 2006}
}