Development of Low Molecular Weight HIV Protease Inhibitor for Oral Use

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The human immunodeficiency virus (HIV) codes for an aspartic portease known to be essential for retroviral maturation and replication. The HIV protease can recognize Phe-Pro and Tyr-Pro sequences as the virus-specific cleavage site. These features provided a basis for the rational design of selective HIV protease-targeted drugs for the treatment of acquired immunodeficiency syndrome (AIDS).Based on the substrate transition state, we designed and synthesized a novel class of HIV protease inhibitors containing an unnatural amino acid, (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid, named allophenylnorstatine (Apns) with a hydroxymethylcarbonyl (HMC) isostere. Among them, the conformationally constrained tripeptide kynostatin (KNI)-272 and its low molecular weight dipeptide analogs were highly selective and superpotent HIV protease inhibitors. For example, 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. Also, KNI-272 and its low molecular weight analogs exhibited in vivo anti-HIV activities in human PBMC-SCID mice.We then converted the above inhibitors into soluble prodrugs in order to improve the solubility in water. We found that the prodrugs based on "O-N intramolecular acyl migration" had good solubility in water and could be converted into active form in PBS (pH7.4). These results show that the prodrugs can be administrated by intravenously or oraly without special techniques.