Active Site and Allosteric Inhibitors of the Ribonuclease H Activity of HIV Reverse Transcriptase

Abstract

Despite the wealth of information available for the reverse transcriptase (RT)-associated ribonuclease H (RNaseH) domain of lentiviruses, gammaretroviruses and long terminal repeat containing retrotransposons, exploiting this information in the form of an RNaseH inhibitor with high specificity and low cellular toxicity has been disappointing. However, it is now becoming increasingly evident that the two-subunit HIV-1 RT is a highly versatile enzyme, undergoing major structural alterations in order to interact with, position and ultimately hydrolyze the RNA component of an RNA/DNA hybrid. Thus, in addition to targeting the RNaseH active site, identifying small molecules that bind elsewhere and disrupt catalysis allosterically by impairing conformational flexibility is gaining increased attention. This review summarizes current progress towards development of both active site and allosteric RNaseH inhibitors.

Computational study on the interaction between CCR5 and HIV-1 entry inhibitor maraviroc: insight from accelerated molecular dynamics simulation and free energy calculation

“…Free energy calculations are performed to profile the energetic change during the dissociation process of Maraviroc. Our results can supply useful information to 4 understand the interaction mechanism of Maraviroc in the pocket of CCR5 and to design of more potent inverse agonist of CCR5.…”

Double-Winged 3-Hydroxypyrimidine-2,4-diones: Potent and Selective Inhibition against HIV-1 RNase H with Significant Antiviral Activity

“…Accordingly, reported RNase H inhibitors typically entail a pharmacophore core similar to integrase strand transfer inhibitors (INSTIs) featuring a chelating triad (Figure 1b). 13 Chemotypes known for active site RNase H inhibition include 2-hydroxyisoquinolinedione (HID, 1 ), 14-16 β -thujaplicinol ( 2 ), 17 dihydroxycoumarin ( 3 ), 18 diketoacid ( 4 ), 19 pyrimidinol carboxylic acid ( 5 ), 20 hydroxynaphthyridine ( 6 ) 21 and pyridopyrimidone 7 . 22 Such a strategy has proved viable in achieving potent RNase H inhibition in biochemical assays.…”

Identification of Highly Conserved Residues Involved in Inhibition of HIV-1 RNase H Function by Diketo Acid Derivatives

“…This RNA removal is performed by the RT-associated RNase H function through a sequence of highly specific hydrolytic events. Since the RNase H function is essential for viral replication (5), it has been explored as a drug target, and a number of RNase H inhibitors (RHIs) have been reported (6)(7)(8). RHIs can be classified based on their binding sites, i.e., (i) RHIs that coordinate the two Mg 2ϩ catalytic cofactors at the RNase H active site, such as N-hydroxyimides (9), hydroxytropolones (10), hydroxypyrimidines (11), naphthyridinones (12), nitrofuran-2-carboxylic acid carbamoylmethyl esters (13), hydroxyquinolinones (14), and thiocarbamates and triazoles (15), or (ii) allosteric RHIs, such as vinylogous ureas (16), thienopyrimidinones (17), hydrazones (18), anthraquinones (19), isatines (20,21), and propenones (22).…”