Rational design and synthesis of a novel class of active site-targeted HIV protease inhibitors containing a hydroxymethylcarbonyl isostere. Use of phenylnorstatine or allophenylnorstatine as a transition-state mimic.
A novel class of HIV-1 protease inhibitors containing a hydroxymethylcarbonyl (HMC) isostere were designed from the substrate transition state and synthesized. Phenylnorstatine [Pns; (2R,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] and the 2S diastereomer, (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine (Apns) were effective transition-state mimics, and incorporation of Pns-Pro or Apns-Pro at the P1-P1' site gave potent and specific HIV-1 protease inhibitors. In the inhibitory assays, the chemically synthesized [Ala67,95] HIV-1 protease was used.
Mimoto
T
T
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Japan.
Imai
J
J
Tanaka
S
S
Hattori
N
N
Takahashi
O
O
Kisanuki
S
S
Nagano
Y
Y
Shintani
M
M
Hayashi
H
H
Sakikawa
H
H
D000595:Amino Acid Sequence; D001665:Binding Sites; D017320:HIV Protease Inhibitors; D008969:Molecular Sequence Data; D010654:Phenylbutyrates / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry
D017320:HIV Protease Inhibitors; D010654:Phenylbutyrates; D011480:Protease Inhibitors; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid