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 A 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.affiliation: Department of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Perali Ramu
authors.initials: PR
authors.lastname: Sridhar
authors.forename: Sofiya
authors.initials: S
authors.lastname: Leshchenko
authors.forename: Azhar K
authors.initials: AK
authors.lastname: Hussain
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Li
authors.forename: Andrey Yu
authors.initials: AY
authors.lastname: Kovalevsky
authors.forename: D Eric
authors.initials: DE
authors.lastname: Walters
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Wedekind
authors.forename: Valerie
authors.initials: V
authors.lastname: Grum-Tokars
authors.forename: Debananda
authors.initials: D
authors.lastname: Das
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Gatanaga
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D018360:Crystallography, X-Ray; D000069454:Darunavir; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects*; D016333:HIV Protease / Q000187:drug effects*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C513857:5-hydroxyhexahydrocyclopenta(b)furan; D019086:Bridged Bicyclo Compounds, Heterocyclic; C513858:GRL 06579A; D017320:HIV Protease Inhibitors; D008024:Ligands; D013449:Sulfonamides; D016333:HIV Protease; D000069454:Darunavir