2. Academic Validation
  3. Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV

Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV

  • J Med Chem. 2008 May 22;51(10):2992-3004. doi: 10.1021/jm701555p.
Shingo Nakatani 1,  Koushi Hidaka,  Ei'ichi Ami,  Koichiro Nakahara,  Akihiko Sato,  Jeffrey-Tri Nguyen,  Yoshio Hamada,  Yasuko Hori,  Nobuyuki Ohnishi,  Akinori Nagai,  Tooru Kimura,  Yoshio Hayashi,  Yoshiaki Kiso
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
PMID: 18426195 DOI: 10.1021/jm701555p
Abstract

Several non-natural D-amino acid derivatives were introduced as P2/P3 residues in allophenylnorstatine-containing (Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid) HIV Protease Inhibitors. The synthetic analogues exhibited potent inhibitory activity against HIV-1 protease Enzyme and HIV-1 replication in MT-4 cells. Structure-activity relationships revealed that D-cysteine or serine derivatives contributed to highly potent anti-HIV activities. Interestingly, anti-HIV activity of all the D-amino acid-introduced inhibitors was remarkably enhanced in their anti-HIV activities against a Nelfinavir-resistant clone, which has a D30N mutation in the protease, over that of the wild-type strain. HIV inhibitory activity of several analogues was moderately affected by an inclusion of alpha1-acid glycoprotein in the test medium.

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