Abstract
Despite great efforts have been made in the prevention and therapy of human immunodeficiency virus (HIV-1) infection, however the difficulty to eradicate latent viral reservoirs together with the emergence of multi-drug-resistant strains require the search for innovative agents, possibly exploiting novel mechanisms of action. In this context, the HIV-1 reverse transcriptase (RT)-associated ribonuclease H (RNase H), which is one of the few HIV-1 encoded enzymatic function still not targeted by any current drug, can be considered as an appealing target. In this work, we repurposed in-house anti-influenza derivatives based on the 1,2,4-triazolo[1,5-a]-pyrimidine (TZP) scaffold for their ability to inhibit HIV-1 RNase H function. Based on the results, a successive multi-step structural exploration around the TZP core was performed leading to identify catechol derivatives that inhibited RNase H in the low micromolar range without showing RT-associated polymerase inhibitory activity. The antiviral evaluation of the compounds in the MT4 cells showed any activity against HIV-1 (IIIB strain). Molecular modelling and mutagenesis analysis suggested key interactions with an unexplored allosteric site providing insights for the future optimization of this class of RNase H inhibitors.
Highlights
Since the isolation and identification of the human immunodeficiency virus (HIV-1) as the cause of AIDS, extensive research work has been carried out that has led to 28 anti-HIV-1 drugs blocking different steps and targets within the HIV-1 replicative cycle
Some of them are dual inhibitors active against both the reverse transcriptase (RT)-associated enzymatic functions while others emerged as selective RNase H inhibitors (RNHIs)
No inhibitor of the RT-associated ribonuclease H (RNase H) activity progressed to clinic so far
Summary
Since the isolation and identification of the human immunodeficiency virus (HIV-1) as the cause of AIDS, extensive research work has been carried out that has led to 28 anti-HIV-1 drugs blocking different steps and targets within the HIV-1 replicative cycle. Their use as combination antiretroviral therapy (cART) permitted to achieve an impressive progress in the treatment and management of HIV-1 infection, revolutionizing its consideration from a death sentence to a chronic but controllable illness [1]. This event relies on the concerted activity of the two main distinct associated activities that RT possesses: RNA- and DNA-dependent
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