Kiso Y, Mimoto T, Enomoto H, Kisanuki S, Moriwaki H, Kimura T, Hattori N, Hayashi H, Takada K, Akaji K; International Conference on AIDS.
Int Conf AIDS. 1994 Aug 7-12; 10: 105 (abstract no. PA0299).
Department of Medicinal Chemistry, Kyoto Pharmaceutical University, Japan.
The HIV protease, an aspartic protease, can recognize Phe-Pro and Tyr-Pro sequences as the virus specific cleavage sites. Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing allophenylnorstatine (Apns). Among them, the conformationally constrained tripeptide kynostatin (KNI)-272 (iQoa-Mta-Apns-Thz-NHBut) was a highly selective and super-potent HIV protease inhibitor (Ki = 0.0055 nM). KNI-272 exhibited potent antiviral activities against both AZT-sensitive and -insensitive clinical HIV-1 isolates as well as HIV-2 with low cytotoxicity. After i.d. administration, bioavailability of KNI-272 was 42.3% in rats. The practical efficient synthetic method was established. Because of the proximity to the virus specific substrate transition state, KNI-272 satisfies the requirements for anti-AIDS drugs: 1. in vitro enzyme inhibition (potency, mechanism, selectivity and stability); 2. antiviral activity in cells (potency, mechanism, cytotoxicity, stability and permeability); 3. in vivo animal tests (toxicity, stability and oral bioavailability).
Publication Types:
Keywords:
- 3-amino-2-hydroxy-4-phenylbutanoic acid
- Animals
- Antiviral Agents
- Dipeptides
- HIV Protease
- HIV Protease Inhibitors
- HIV-1
- HIV-2
- In Vitro
- Oligopeptides
- Phenylbutyrates
- Proline
- Rats
- Zidovudine
- kynostatin 272
- tyrosyl-proline
Other ID:
UI: 102209848
From Meeting Abstracts