Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase: from the Biology of Reverse Transcription to Molecular Design

Abstract

Replication of human immunodeficiency virus 1 (HIV-1) uses a viral reverse transcriptase (RT) to convert its positive-strand RNA into double stranded DNA, which is then integrated into host genome. Reverse transcription is a complex event involving p66 and p51 RT subunits but also several viral proteins including Nef, Tat, Vif, IN, NCp7 and p55gag. Viral RNA itself forms a primer/template complex by association with a cellular tRNA(Lys3) which is already present in mature virions. A RT initiation complex (RTIC) is thus formed which may also involve cellular protein upon viral entry. X rays diffraction and NMR studies of free or inhibitor-bound RT have led to the recognition of RT 3D structure, and allowed a thorough understanding of the mode of action of classical competitive nucleoside RT inhibitors (NRTIs) and of the binding of allosteric, non NRTIs (NNRTIs) inhibitors. This also opened an access to computer-aided drug design and modeling. Current NNRTIs represent, in terms of chemical structures, a heterogeneous class of inhibitors currently undergoing extensive development. By contrast with NRTIs, they seem to block initiation steps of reverse transcription. Molecular dynamics, detailed analysis of their interaction with RT as well as the incidence, in the series, of cases of non classical biological behavior, as illustrated here for a new family of compounds, suggest mechanisms of action which are not understandable without considering the involvement of the RTIC as a whole. This opens the exciting perspective of developing new compounds based on this integrated knowledge. Key Words: Nonnucleoside reverse transcriptase inhibitors (NNRTIs); Reverse transcriptase initiation complex (RTIC); Human immunodeficiency virus (HIV); Non classical nonnucleoside reverse transcriptase inhibitors; Molecular modeling; Docking; QSAR; Natural endogenous reverse transcription (NERT).

QSAR models and scaffold-based analysis of non-nucleoside HIV RT inhibitors

“…Pyrimidine derivatives were synthesized for decades and have been actively pursued as NNRTIs [3]. Two main series of pyrimidine derivatives are DABO (Dihydro-alkoxy-benzyloxopyrimidine) and DAPY (Di aryl pyrimidine) [2]. Owing to NNRTIs importance in targeting HIV RT, QSAR studies have been used to understand the relationship between its structure and anti-HIV RT activity.…”

Conformational Changes in HIV-1 Reverse Transcriptase Induced by Nonnucleoside Reverse Transcriptase Inhibitor Binding

“…Second generation NNRTIs tend to be more potent than the first generation compounds, and in general are more active against a broader spectrum of drug-resistant strains of HIV-1 [11]. Analysis of the available structural data indicates a number of common features of the NNRTI pharmacophores important for interaction with the RT NNRTI-BP [41,72]. These include an aromatic ring capable of π-stacking interactions, NH-C=O or NH-C=S groups able to participate in hydrogen bonding, and one or more hydrocarbon-rich region that participate in hydrophobic contacts.…”

Profile of disposition, tissue distribution and excretion of the novel anti-human immunodeficiency virus (HIV) agent W-1 in rats

“…NNRTIs, different from NRTIs, have a definitive place in clinical treatment of AIDS because of their low toxicity, high potency and good selectivity (Tronchet and Seman 2003). So far, five NNRTIs are on market for the treatment of HIV infection: nevirapine, delavirdine, efavirenz, etravirine and rilpivirine Fig.…”