A literature review on the human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome (AIDS). This review includes its life cycle, HIV protease structure, function, and substrates, as well as the mechanism and the design of inhibitors including the clinically approved drugs. Moreover the review mentioned the problems that hindered the development of peptidomimetic drug candidates as HIV protease inhibitors and the different approaches used by medicinal chemists to overcome these problems. A special attention was made to the design rationale as well as the lead optimization processes that provided inhibitors that possess high potency, reduced molecular weight and lower lipophilicity of the allophenylnorstatine (Apns) containing HIV protease inhibitors.

Dipeptide analogues incorporating allophenylnorstatine [Apns; (2S,3S)-3amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic at the scissile bond were designed and synthesized in the hope of obtaining a novel KNI series of HIV protease inhibitors. The precursors, N-P2'-3-(2S,3S)-3-(tert-butyloxy-carbonyl)amino-2-hydroxy-4-phenylbutanoyl)-5,5-dimethylthiazolidine-4-carboxamide (N-Boc-Apns-Dmt-P2') 4a-p were prepared by deprotection of the synthones N-P2'-(tert-butyloxycarbonyl)-5,5-dimethylthiazolidine-4-carboxamide (Boc-Dmt-P2') 2a-p, then coupling with (2S,3S)3-(tert-butyloxycarbonyl)amino-2-hydroxy-4-phenylbutanoic acid (N-Boc-Apns-OH) 3. The deprotected intermediates 4 were coupled with the activated carboxyl groups of the P2 ligands to afford the target dipeptides. In this work, we fixed at the P2 site either a 2,6-dimethylphenoxyacetyl or a 3-hydroxy-2-methylbenzoyl group. Substitutes at the P2' site were varied to afford the members of the series 7 and 8. Improved activity of most of the members of series 8 relative to their analogues of series 7 can be partially attributed to the differences in the structures of the P2 moieties. Positional isomerism in the P2' moieties significantly affected the activity and polarity of the target.

A Novel Dipeptide-Based HIV Protease Inhibitor Containing Allophenylnorstatine. -A large variety of derivatives related to the lead substances KNI-577 (Ia) and KNI-901 (IIa) are prepared and investigated for their structure-activity profile. Only derivatives (Ib) and (IIb) reveal analogous or slightly higher activity, thus being promising candidates for further investigations. -(ABDEL-RAHMAN, H. M.; EL-KOUSSI*, N. A.; ALKARAMANY, G. S.; YOUSSEF, A. F.; KISO, Y.; Arch.

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The design and development of potent HIV protease inhibitors remain an attractive target for antiviral therapy. A novel class of HIV protease inhibitors containing allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic have been reported. In this work we fixed P 2` (as tert-butylamino or 2-methylbenzylamino) and changed P 2 moiety to provide two series of dipeptide analogs. Preliminary evaluation of the activity of the synthesized derivatives were determined as percentage of enzyme inhibition at 5 M level. The results showed that the introduction of 2-methylbenzylamino moiety as P 2` ligand 6a-e considerably improved HIV inhibitory activity in comparison with the tert-butyl amino analogs 5a-e. It was found that compounds in both series retained activity still less than the lead compounds KNI-577 and KNI-727.