title: Design and synthesis of broad-based mono- and bi- cyclic inhibitors of FIV and HIV proteases.
abstract: Based on the substrate transition state and our strategy to tackle the problem of drug resistance, a series of HIV/FIV protease (HIV /FIV PR) monocyclic inhibitors incorporating a 15- or 17-membered macrocycle with an equivalent P3 or P3' group and a unique unnatural amino acid, (2R, 3S)-3-amino-2-hydroxy-4-phenylbutyric acid, have been designed and synthesized. In addition, based on the structure of TL3 with small P3/P3' group, we have synthesized two conformationally restricted bicyclic inhibitors containing the macrocycle, which mimic the P1/P1'-P3/P3' tripeptide [Phe-Val-Ala] of TL3. We have found that the contribution of the macrocycle in our monocyclic inhibitors is important to the overall activity, but the ring size does not affect the activity to a significant extent. Several inhibitors that were developed in this work, exhibit low nanomolar inhibitory activity against the wild-type HIV/FIV PR and found to be highly effective against some drug-resistant as well as TL3-resistant mutants of HIV PRs. Compound 15, in particular, is the most effective cyclic inhibitor in hand to inhibit FIV replication in tissue culture at a concentration of 1.0 micro g/mL (1.2 microM).
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550North Torrey Pines Road, La Jolla, CA 92037, USA. wong@scripps.edu
authors.forename: Chi Ching
authors.initials: CC
authors.lastname: Mak
authors.forename: Ashraf
authors.initials: A
authors.lastname: Brik
authors.forename: Danica L
authors.initials: DL
authors.lastname: Lerner
authors.forename: John H
authors.initials: JH
authors.lastname: Elder
authors.forename: Garrett M
authors.initials: GM
authors.lastname: Morris
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015195:Drug Design; D016333:HIV Protease / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C095555:FIV protease; D016333:HIV Protease