HIV-1 RT Inhibitors with a Novel Mechanism of Action: NNRTIs that Compete with the Nucleotide Substrate

Giovanni Maga,Eric Ennifar,Maurizio Botta,Marco Radi,Marie-Aline Gerard

doi:10.3390/v2040880

Abstract

HIV-1 reverse transcriptase (RT) inhibitors currently used in antiretroviral therapy can be divided into two classes: (i) nucleoside analog RT inhibitors (NRTIs), which compete with natural nucleoside substrates and act as terminators of proviral DNA synthesis, and (ii) non-nucleoside RT inhibitors (NNRTIs), which bind to a hydrophobic pocket close to the RT active site. In spite of the efficiency of NRTIs and NNRTIs, the rapid emergence of multidrug-resistant mutations requires the development of new RT inhibitors with an alternative mechanism of action. Recently, several studies reported the discovery of novel non-nucleoside inhibitors with a distinct mechanism of action. Unlike classical NNRTIs, they compete with the nucleotide substrate, thus forming a new class of RT inhibitors: nucleotide-competing RT inhibitors (NcRTIs). In this review, we discuss current progress in the understanding of the peculiar behavior of these compounds.

Highlights

Current treatments against human immunodeficiency virus type 1 (HIV-1) infections include six different classes of drugs, targeting the three viral enzymes, the virus fusion process or viral entry [1]
The development of INDOPYs and DAVPs led to the identification of “Nucleotide-competing reverse transcriptase (RT)
Inhibitors” (NcRTIs), a new class of RT Inhibitors endowed with a novel mechanism of action

Summary

Introduction

Current treatments against human immunodeficiency virus type 1 (HIV-1) infections include six different classes of drugs, targeting the three viral enzymes (more than 20 different compounds in clinical use target the protease, reverse transcriptase and integrase), the virus fusion process (enfuvirtide/T-20 targets the viral gp41) or viral entry (maraviroc targets the human CCR5 cellular coreceptors) [1]. In vitro enzymatic experiments based on inhibition of DNA synthesis led to the conclusion that both compounds were targeting the reverse transcription step of HIV-1 replication In spite of their non-nucleosidic chemical structure (Figure 2), several features of indolopyridones (INDOPYs) were clearly inconsistent with their classification as NNRTIs, calling for more investigations of their mechanism of action. As a result from these kinetic studies, it appears that the binding of DAVP-1 to the free enzyme or to the RT/primer-template binary complex is more stable than to the RT/primer-template/dNTP complex This peculiar behavior excludes a classical competitive inhibition mechanism for DAVPs, resulting only from a binding of the inhibitor to the polymerase catalytic site of the binary complex, as for NRTIs. DAVP-1 was shown to be highly active in cell-free assays, its antiviral efficiency remains to be tested in cell-based assays.

Structural Biology Studies of NcRTIs

Conclusions