Combination of non-natural D-amino acid derivatives and allophenylnorstatine-dimethylthioproline scaffold in HIV protease inhibitors have high efficacy in mutant HIV.
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.
Nakatani
Shingo
S
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Hidaka
Koushi
K
Ami
Ei'ichi
E
Nakahara
Koichiro
K
Sato
Akihiko
A
Nguyen
Jeffrey-Tri
JT
Hamada
Yoshio
Y
Hori
Yasuko
Y
Ohnishi
Nobuyuki
N
Nagai
Akinori
A
Kimura
Tooru
T
Hayashi
Yoshio
Y
Kiso
Yoshiaki
Y
D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008958:Models, Molecular; D009154:Mutation; D010654:Phenylbutyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000596:Amino Acids; D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; D013844:Thiazoles; C065579:5,5-dimethylthiazolidine-4-carboxylic acid; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1