Design and synthesis of substrate-based peptidomimetic human immunodeficiency virus protease inhibitors containing the hydroxymethylcarbonyl isostere

✍ Scribed by Yoshiaki Kiso

• Publisher: Wiley (John Wiley & Sons)
• Year: 1996
• Tongue: English
• Weight: 759 KB
• Volume: 40
• Category: Article
• ISSN: 0006-3525
• DOI: 10.1002/(sici)1097-0282(1996)40:2<235::aid-bip3>3.0.co;2-x

✦ Synopsis

Peptidomimetic Human

The human immunodeficiency virus (HIV) codas f o r an u.spartic protease known to be essential $)r retroviral mat urution and replicution. The H I V proteuw can rmignize Phe-Pro and Tyr-Pro sequences as the virus-specific cleuvuge site. These.fi.atures provided a basisJor the rational design of selective HI Vprotease-lurgeted drugs,fi)r the treatment ofacquired immunod&iency syndrome (AIDS). HIV protouse is ,formed,Jrom two identical 99 amino acid peptides. I.I/L. replaced the two Cys residues by L-AIU to .synthesizr [Aho7." ] -HIV-1 protease by the solid 1 protease (NY-5 isolate) using the thioester chemical ligation method. Based on the .substrate transition state, we designed and synthesizeda novel cla.ss ofHI Vproteuse inhibitors containing an unnatural amino acid, ( 2 S , 3s) -3-amino-2-hydrox.v-4-phcnylbu~yuic acid, named allophenylnorstutine (Apns) with a hydrox.vmethyIcarbonyl (HMC) isosterc. Among them, the conformationally constrained tripeptide kynostutin ( K N I ) -272 (iQou-Mtu-Apns-Thz-NHBu') was a highly selective and superpotent HI Vprotease inhibitor (Ki = 0.0055 nM). KNI-272 exhibited potent antiviral activities against both AZT-sensitive and -insensitive clinical HIV-1 isolates as well us HIV-2 with low cytotoxicity. Ajer i.d. administration, bioavailability qf KNI-272 was 42.3% in rats. Also, KNI-272 exhibited in vivo anti-HIV activities in human PBMC-SCID mice. The x-ray crystallography and molecular modeling studies showed that the HMC group in KNI-272 interacted excellently wilh the aspartic acid carboxyl groiips of HIVproteuse active site in the essentially same hydrogen-bonding mode us the trunsition state. This result implies that the H M C isostere is an ideal transition-stutc mimic and contrihtes to the high activity of phase method and then preparcd [ Tyro.4', Nle36,46, (NHCH2c'OSc'H2CO)-~'-~~, AIU'~.~' 1 H I v-