KNI‐577, a Potent Small‐Sized HIV Protease Inhibitor Based on the Dipeptide Containing the Hydroxymethylcarbonyl Isostere as an Ideal Transition‐State Mimic

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].