title: Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multidrug resistant HIV-1 strains.
abstract: Novel HIV protease inhibitors containing a hydroxyethylamine dipeptide isostere as a transition state-mimic king structure were synthesized by combining substructures of known HIV protease inhibitors. Among them, TYA5 and TYB5 were proven to be not only potent enzyme inhibitors (K(i) = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC(50) = 9.5 nM and 66 nM, respectively), even against viral strains with multidrug resistance. Furthermore, insertion of an (E)-alkene dipeptide isostere at the P(1)-P(2) position of TYB5 led to development of a purely nonpeptidic protease inhibitor, TYB1 (K(i) = 0.38 nM, IC(50) = 160 nM).
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Tamamura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Koh
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueda
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Tomonori
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Manabu
authors.initials: M
authors.lastname: Aoki
authors.forename: Kenji
authors.initials: K
authors.lastname: Maeda
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Watai
authors.forename: Hisashi
authors.initials: H
authors.lastname: Arikuni
authors.forename: Akira
authors.initials: A
authors.lastname: Otaka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Fujii
mesh_terms: D004151:Dipeptides / Q000737:chemistry*; D024921:Drug Resistance, Multiple, Viral; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000302:isolation & purification; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018716:Molecular Mimicry; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D004151:Dipeptides; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D009281:Naphthalenes; D013449:Sulfonamides