A computational overview of integrase strand transfer inhibitors (INSTIs) against emerging and evolving drug-resistant HIV-1 integrase mutants

Abstract

AIDS (Acquired immunodeficiency syndrome) is one of the chronic and potentially life-threatening epidemics across the world. Hitherto, the non-existence of definitive drugs that could completely cure the Human immunodeficiency virus (HIV) implies an urgent necessity for the discovery of novel anti-HIV agents. Since integration is the most crucial stage in retroviral replication, hindering it can inhibit overall viral transmission. The 5 FDA-approved integrase inhibitors were computationally investigated, especially owing to the rising multiple mutations against their susceptibility. This comparative study will open new possibilities to guide the rational design of novel lead compounds for antiretroviral therapies (ARTs), more specifically the structure-based design of novel Integrase strand transfer inhibitors (INSTIs) that may possess a better resistance profile than present drugs. Further, we have discussed potent anti-HIV natural compounds and their interactions as an alternative approach, recommending the urgent need to tap into the rich vein of indigenous knowledge for reverse pharmacology. Moreover, herein, we discuss existing evidence that might change in the near future. Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00203-023-03461-8.

Synthesis of 5-Aroyl-2-aryl-3-hydroxypyridin-4(1H)-ones

“…(Figure 1), possess a 3,4-HPO structural motif designed to coordinate magnesium ions of HIV integrase and thus prevent integration of the viral DNA [9][10][11][12][13][14][15]. Additionally, the inhibitors of catechol-O-methyltransferase (contains Mg 2+ ) [16], human cytomegalovirus pUL89 protein (Mn 2+ ) [17], and influenza cap-dependent endonuclease (Mn 2+ ) [18] were discovered.…”

“…Additionally, 3-hydroxy-4-pyridones have recently received considerable attention as promising metal-binding pharmacophores, such as inhibitors of metalloenzymes, and thus are being now intensively investigated to design novel drugs, including antiviral ones [8]. As a result, approved HIV integrase strand transfer inhibitors (INSTI) dolutegravir, bictegravir, and cabotegravir, as well as several newly developed drug candidates (Figure 1), possess a 3,4-HPO structural motif designed to coordinate magnesium ions of HIV integrase and thus prevent integration of the viral DNA [9][10][11][12][13][14][15]. Additionally, the inhibitors of catechol-O-methyltransferase (contains Mg 2+ ) [16], human cytomegalovirus pUL89 protein (Mn 2+ ) [17], and influenza cap-dependent endonuclease (Mn 2+ ) [18] were discovered.…”