Quinolinonyl Non-Diketo Acid Derivatives as Inhibitors of HIV‑1 Ribonuclease H and Polymerase Functions of Reverse Transcriptase

Novel anti-HIV agents
are still needed to overcome resistance issues,
in particular inhibitors acting against novel viral targets. The ribonuclease
H (RNase H) function of the reverse transcriptase (RT) represents
a validated and promising target, and no inhibitor has reached the
clinical pipeline yet. Here, we present rationally designed non-diketo
acid selective RNase H inhibitors (RHIs) based on the quinolinone
scaffold starting from former dual integrase (IN)/RNase H quinolinonyl
diketo acids. Several derivatives were synthesized and tested against
RNase H and viral replication and found active at micromolar concentrations.
Docking studies within the RNase H catalytic site, coupled with site-directed
mutagenesis, and Mg2+ titration experiments demonstrated
that our compounds coordinate the Mg2+ cofactor and interact
with amino acids of the RNase H domain that are highly conserved among
naïve and treatment-experienced patients. In general, the new
inhibitors influenced also the polymerase activity of RT but were
selective against RNase H vs the IN enzyme.