HIV-1 Reverse Transcriptase Still Remains a New Drug Target: Structure, Function, Classical Inhibitors, and New Inhibitors with Innovative Mechanisms of Actions

Abstract

During the retrotranscription process, characteristic of all retroviruses, the viral ssRNA genome is converted into integration-competent dsDNA. This process is accomplished by the virus-coded reverse transcriptase (RT) protein, which is a primary target in the current treatments for HIV-1 infection. In particular, in the approved therapeutic regimens two classes of drugs target RT, namely, nucleoside RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). Both classes inhibit the RT-associated polymerase activity: the NRTIs compete with the natural dNTP substrate and act as chain terminators, while the NNRTIs bind to an allosteric pocket and inhibit polymerization noncompetitively. In addition to these two classes, other RT inhibitors (RTIs) that target RT by distinct mechanisms have been identified and are currently under development. These include translocation-defective RTIs, delayed chain terminators RTIs, lethal mutagenesis RTIs, dinucleotide tetraphosphates, nucleotide-competing RTIs, pyrophosphate analogs, RT-associated RNase H function inhibitors, and dual activities inhibitors. This paper describes the HIV-1 RT function and molecular structure, illustrates the currently approved RTIs, and focuses on the mechanisms of action of the newer classes of RTIs.

Identification of mechanistically distinct inhibitors of HIV-1 reverse transcriptase through fragment screening

“…Our fragment screen and substructure analysis of one hit identified a total of seven active fragments that are chemically dissimilar to all other known HIV-1 RT inhibitors (Binding DB; www.bindingdb.org) (4,7,15), including those HIV-1 RT inhibitors identified in two previously published FBDD programs that used either SPR-based (16) or X-ray crystallography-based (6) screening. Three of the seven scaffolds that we identified have activities consistent with their ability to bind to sites distinct from the NNIBP on the HIV-1 RT, with one of these fragments inhibiting HIV-1 replication in cell culture at the reverse transcription step.…”

“…To determine that the hits represented new chemical scaffolds for HIV-1 RT inhibitors, a Tanimoto similarity search was performed to compare our seven hits with the 1,531 RT inhibitors recorded in the Binding DB (4,15,19,20) and with fragments identified in previous FBDD screens for HIV-1 RT inhibitors: the nine fragments reported by Bauman et al (6) and the bromoindanone NNRTI identified by Geitmann et al (16). A Tanimoto score of 80% or greater is generally regarded as high structural similarity.…”

“…HIV reverse transcriptase (RT) plays an essential role in the virus life cycle and was the first successful enzyme target for HIV therapy (4). The HIV-1 RT is a heterodimer composed of 66-kDa (p66) and 51-kDa (p51) polypeptides that converts the single-stranded viral genomic RNA into a double-stranded proviral DNA precursor through RNA-and DNA-dependent polymerase and RNase H enzymatic activities (4).…”

“…The HIV-1 RT is a heterodimer composed of 66-kDa (p66) and 51-kDa (p51) polypeptides that converts the single-stranded viral genomic RNA into a double-stranded proviral DNA precursor through RNA-and DNA-dependent polymerase and RNase H enzymatic activities (4). Thirteen of the 26 approved anti-HIV drugs act on HIV-1 RT, and there are ongoing efforts to identify new RT inhibitors (4). Only two classes of drugs targeting this enzyme are in clinical use: nucleoside/nucleotide RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs).…”

“…Only two classes of drugs targeting this enzyme are in clinical use: nucleoside/nucleotide RT inhibitors (NRTIs) and nonnucleoside RT inhibitors (NNRTIs). NRTIs are prodrugs that structurally mimic the natural substrates of HIV-1 RT, deoxyribonucleoside triphosphates (dNTPs), but normally lack a 3′-hydroxyl group on the ribose sugar, causing chain termination during nucleic acid synthesis (4). NNRTIs are structurally diverse compounds that inhibit DNA polymerization by binding to an allosteric NNRTI binding pocket (NNIBP) in HIV-1 RT (4).…”