jm020537i_si_002.pdf (343.88 kB)
Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains
journal contribution
posted on 2003-03-18, 00:00 authored by Hirokazu Tamamura, Yasuhiro Koh, Satoshi Ueda, Yoshikazu Sasaki, Tomonori Yamasaki, Manabu Aoki, Kenji Maeda, Yoriko Watai, Hisashi Arikuni, Akira Otaka, Hiroaki Mitsuya, Nobutaka FujiiNovel 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
(Ki = 0.12 nM and 0.10 nM, respectively) but also strong anti-HIV agents (IC50 = 9.5 nM and
66 nM, respectively), even against viral strains with multidrug resistance. Furthermore,
insertion of an (E)-alkene dipeptide isostere at the P1−P2 position of TYB5 led to development
of a purely nonpeptidic protease inhibitor, TYB1 (Ki = 0.38 nM, IC50 = 160 nM).