Reduction of peptide character of HIV protease inhibitors that exhibit nanomolar potency against multidrug resistant HIV-1 strains.
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).
Tamamura
Hirokazu
H
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. tamamura@pharm.kyoto-u.ac.jp
Koh
Yasuhiro
Y
Ueda
Satoshi
S
Sasaki
Yoshikazu
Y
Yamasaki
Tomonori
T
Aoki
Manabu
M
Maeda
Kenji
K
Watai
Yoriko
Y
Arikuni
Hisashi
H
Otaka
Akira
A
Mitsuya
Hiroaki
H
Fujii
Nobutaka
N
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
D004151:Dipeptides; D017320:HIV Protease Inhibitors; D007546:Isoquinolines; D009281:Naphthalenes; D013449:Sulfonamides