KNI-577, a potent small-sized HIV protease inhibitor based on the dipeptide containing the hydroxymethylcarbonyl isostere as an ideal transition-state mimic.

Abstract

The development of an effective therapeutic agent for the treatment of AIDS continues to be a challenging problem. Since the discovery that the virally encoded HIV protease is vital for propagation, inhibition of this enzyme has become a major target for AIDS chemotherapy. Consequently, numerous efforts aimed at the development of potent and selective inhibitors have been undertaken[2]. Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] with a hydroxymethylcarbonyl (HMC) isostere. Among them, the tripeptide KNI-272 was a highly selective and superpotent HIV protease inhibitor (Ki=5.5 pM)[3]. KNI-272 exhibited potent in vitro and in vivo antiviral activities with low cytotoxicity[4]. The NMR, X-ray crystallography, and molecular modeling studies showed that the HMC group in KNI-272 interacted excellently with the aspartic acid carboxyl groups of the HIV protease active site[5].