Abstract

The peptidomimetic-based design and synthesis of HIV-1 protease and other entry inhibitors are generally oriented to block the viral receptor functionalities in the host cells. Most of the drugs classified under HIV-1 protease inhibitors are primarily optimized through substrate-based design strategies. The peptidomimetic drugs present in the market are non-hydrolyzable by the catalytic aspartic acid residues, an indispensable approach still used in designing potential pharmacophores for protease inhibitors. Thus, a variety of amino acid-containing hybrid small molecules are tested against the HIV-1 protease enzyme by incorporating essential fragments required to block protease functionalities. However, the appearance of mutations in HIV polyproteins is a key parameter to be seriously considered while designing peptidomimetics. Hence, comprehensive knowledge regarding HIV peptidomimetic/medicinal chemistry along with optimization strategy and organic synthesis awareness is critical in the current scenario. The present chapter is aimed to provide in-depth literature on medicinally optimized HIV-1 protease inhibitors, TatTAR RNA blockers with their synthesis, and later it is expanded to the peptidomimetics (entry inhibitors) involved in the envelope glycoprotein (gp120/gp41) and capsid inhibitors. Furthermore, the knowledge-based classification of HIV-1 protease inhibitors, anti-dimer agents, Tat-TAR RNA blockers, and entry inhibitors, along with their synthetic procedures, would serve as a single model template for scientific as well as academic research towards the development of anti-HIV peptidomimetics.