HIV-1 RT-Associated RNase H Function Inhibitors: Recent Advances in Drug Development

Abstract

The HIV-1 genomic RNA reverse transcription is an essential step in the virus cycle carried out by the viral-coded reverse transcriptase (RT), which has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) function and the ribonuclease H (RNase H) function. The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. The RT associated activities are both essential for HIV-1 replication and validated targets for drug development, but only the polymerase function has been widely investigated as drug target. In fact, either nucleoside or non-nucleoside RT inhibitors currently used in therapy act on the polymerase associated activity. In this review, we describe the compounds, reported up to today, which inhibit the HIV-1 RNase H function, their chemical structures, the structure-activity relationships and the mechanism of action.

New Anthraquinone Derivatives as Inhibitors of the HIV-1 Reverse Transcriptase-Associated Ribonuclease H Function

“…RNase H hydrolytic activity is required to remove viral RNA during and following minus-strand DNA synthesis, as well as to specifically remove tRNA Lys3 and polypurine tracts, the primers for minus- and plus-strand DNA synthesis, respectively [2]. This activity is a promising target for developing highly specific inhibitors for treatment of HIV-1-infected individuals [3,4]. …”

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).…”

Inhibition of the Ribonuclease H Activity of HIV-1 Reverse Transcriptase by GSK5750 Correlates with Slow Enzyme-Inhibitor Dissociation

“…This architecture has driven the design of small molecule inhibitors of RNase H activity. Several distinct chemical compounds with a three-oxygen pharmacophore, or equivalent structures that are capable of chelating the two catalytic metal ions have been described (20,21). As such, these compounds are generally referred to as active site RNase H inhibitors.…”