Small-Sized Peptides Containing (APNS)Residue As HIV-1 Protease Inhibitors

The submitted thesis is prefaced by 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 peptidominetic drug candidates as HIV protease inhibitors and the different approaches used to overcome these problems.A special attention was made to the allophenylnorestatine (Apns)-containing HIV protease inhibitors, their design rationale as well as the lead optimization processes that provided the key lead compounds KNI-272, KNI-577 and KNI-727.In the present study, in an effort to identify inhibitors that possess high potency, reduced molecular weight and lower lipophilicity, small-sized HIV protease inhibitors with suitable P2 and P2 modifications were prepared, and the structure-activity relationship were discussed.Compounds were synthesized by the solution method in a stepwise manner. The final products were purified by preparative HPLC and obtained as lyophilized materials. Assignment of the chemical structure of the synthesized compounds was based on FAB-MS, 1H NMR, and optical activity. The purity was confirmed by TLC, HPLC, and high resolution FAB-MS.