title: Structure-activity studies of FIV and HIV protease inhibitors containing allophenylnorstatine.
abstract: The interaction of P1 and P3 side chains with the combining S1 and S3 hydrophobic subsites of HIV and FIV proteases has been explored using asymmetric competitive inhibitors. The inhibitors evaluated contained (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid (allophenylnorstatine) as the hydroxymethylcarbonyl isostere, (R)-5,5-dimethyl-1, 3-thiazolidine-4-carbonyl as P1', Val as P2 and P2' residues, and a variety of amino acids at the P3 and P3' positions. All inhibitors showed competitive inhibition of both enzymes with higher potency against the HIV protease in vitro. Within this series, 31 (VLE776) is the most effective inhibitor against FIV protease, and it contains Phe at P3, but no P3' residue. VLE776 also exhibited potent antiviral activities against the drug-resistant HIV mutants (G48V and V82F) and the TL3-resistant HIV mutants. Explanation of the inhibition activities was described. In addition, a new strategy was described for development of bifunctional inhibitors, which combine the protease inhibitor and another enzyme inhibitor in one molecule.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: V D
authors.initials: VD
authors.lastname: Le
authors.forename: C C
authors.initials: CC
authors.lastname: Mak
authors.forename: Y C
authors.initials: YC
authors.lastname: Lin
authors.forename: J H
authors.initials: JH
authors.lastname: Elder
authors.forename: C H
authors.initials: CH
authors.lastname: Wong
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D016333:HIV Protease / Q000187:drug effects* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D016296:Mutagenesis / Q000235:genetics; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010654:Phenylbutyrates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D017320:HIV Protease Inhibitors; D009841:Oligonucleotides; D010654:Phenylbutyrates; D011480:Protease Inhibitors; D013844:Thiazoles; C434322:VLE 776; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016282:Aspartic Acid Endopeptidases; C095555:FIV protease; D016333:HIV Protease