jm020537i_si_001.pdf (1.34 MB)

Reduction of Peptide Character of HIV Protease Inhibitors That Exhibit Nanomolar Potency against Multidrug Resistant HIV-1 Strains

Download (1.34 MB)
journal contribution
posted on 18.03.2003 by Hirokazu Tamamura, Yasuhiro Koh, Satoshi Ueda, Yoshikazu Sasaki, Tomonori Yamasaki, Manabu Aoki, Kenji Maeda, Yoriko Watai, Hisashi Arikuni, Akira Otaka, Hiroaki Mitsuya, Nobutaka Fujii
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 (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).

History

Exports