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

T Mimoto; J Imai; S Tanaka; N Hattori; O Takahashi; S Kisanuki; Y Nagano; M Shintani; H Hayashi; H Sakikawa

doi:10.1248/cpb.39.2465

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

Chem Pharm Bull (Tokyo). 1991 Sep;39(9):2465-7. doi: 10.1248/cpb.39.2465.

Authors

T Mimoto¹, J Imai, S Tanaka, N Hattori, O Takahashi, S Kisanuki, Y Nagano, M Shintani, H Hayashi, H Sakikawa, et al.

Affiliation

¹ Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Japan.

PMID: 1804562
DOI: 10.1248/cpb.39.2465

Abstract

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.

MeSH terms

Amino Acid Sequence
Binding Sites
HIV Protease Inhibitors*
Molecular Sequence Data
Phenylbutyrates / chemistry*
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / chemistry

Substances

HIV Protease Inhibitors
Phenylbutyrates
Protease Inhibitors
3-amino-2-hydroxy-4-phenylbutanoic acid