Advancements in development of novel class of HIV protease inhibitors

Protease (PR) inhibitors (PIs) are widely regarded as the most significant agents in the treatment of human immunodeficiency virus (HIV) and have been instrumental in the success of highly active antiretroviral therapy (HAART). The PR enzyme is essential for the viral life cycle, as it cleaves various polyproteins into the individual components necessary for the formation of mature, infectious virions.

We systematically synthesized current evidence which revealed the multifaceted effects of PIs, which can function as entry inhibitors, reverse transcription inhibitors and inhibitors of post-reverse transcription processes.

All currently available PIs are confronted with the challenge of emerging drug-resistant viral strains, necessitating the exploration of novel PIs capable of overcoming this resistance.

This review addresses the current landscape of PIs, the primary PR mutations that confer drug resistance, and identifies three classes of novel PIs that warrant consideration for anti-HIV drug development: (i) novel PIs exhibiting robust inhibitory activity that target the traditional active, non-active and cleavage sites of PR; (ii) novel PIs designed to target drug-resistant PR variants, particularly those associated with multi-drug resistant (MDR) HIV isolates; and (iii) novel PIs that engage multiple stages of HIV replication, thereby enhancing the anti-HIV efficacy of PIs.