Abstract
The persistence of the AIDS epidemic, and the life-long treatment required, indicate the constant need of novel HIV-1 inhibitors. In this scenario the HIV-1 Reverse Transcriptase (RT)-associated ribonuclease H (RNase H) function is a promising drug target. Here we report a series of compounds, developed on the 2-amino-6-(trifluoromethyl)nicotinic acid scaffold, studied as promising RNase H dual inhibitors. Among the 44 tested compounds, 34 inhibited HIV-1 RT-associated RNase H function in the low micromolar range, and seven of them showed also to inhibit viral replication in cell-based assays with a selectivity index up to 10. The most promising compound, 21, inhibited RNase H function with an IC50 of 14 µM and HIV-1 replication in cell-based assays with a selectivity index greater than 10. Mode of action studies revealed that compound 21 is an allosteric dual-site compound inhibiting both HIV-1 RT functions, blocking the polymerase function also in presence of mutations carried by circulating variants resistant to non-nucleoside inhibitors, and the RNase H function interacting with conserved regions within the RNase H domain. Proving compound 21 as a promising lead for the design of new allosteric RNase H inhibitors active against viral replication with not significant cytotoxic effects.
Highlights
The acquired immunodeficiency syndrome (AIDS) pandemic is still one of the major world health concerns
A15 (Figure 1), showed the same dual inhibitor profile, being active against viral replication [40], embracing the promising polypharmacology approach to develop effective drugs less susceptible to the selection of resistant variants [44]. Taking into account this information, we explored the 2-amino-6-trifluoromethyl-3pyridinecarboxylic acid as a central core to design new allosteric ribonuclease H (RNase H) inhibitors endowed with potential dual-target ability
In order to confirm our hypothesis of allosteric binding mode, we firstly examined the possible interaction between selected compounds and the magnesium, used as a cofactor by both the Reverse Transcriptase (RT)-associated enzymatic functions
Summary
The acquired immunodeficiency syndrome (AIDS) pandemic is still one of the major world health concerns. While the highly-active antiretroviral therapy (HAART) allows patients who receive optimum treatment a life-expectation comparable to that of the uninfected population [2,3], the sub-optimal adherence and coverage of seropositive people, coupled with life-long treatment, still cause emergence of drug-resistant variants, that could lead to therapy failure [4], and whose transmission to naïve patient is a major concern and requires an optimized treatment [5,6,7]. RT is a heterodimeric (p66/p51) multifunctional enzyme that acts at the early stage of viral infection by converting the viral single-stranded RNA genome into a double-stranded DNA, with the concerted and dynamic interplay of its enzymatic functions RNA- and DNA-dependent DNA polymerase (RDDP and DDDP, respectively), and RT- associated ribonuclease H (RNase H) [8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
