Update and latest advances in antiretroviral therapy

Menéndez‐Arias, Luis; Delgado, Rafaël

doi:10.1016/j.tips.2021.10.004

Cited by 117 publications

(82 citation statements)

References 81 publications

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“…Treatment with antivirals can result in the selection of resistant viral variants and subsequent therapeutic failure. This has been described extensively in the treatment of (chronic/persistent or acute) viral infections caused by HIV, HBV, HCV, herpesviruses or influenza [14, 15]. Importantly, transmission of resistant viruses has been reported for HIV and influenza [16, 17].…”

Section: Introductionmentioning

confidence: 99%

The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir

Jochmans

Liu²,

Donckers

et al. 2022

Preprint

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The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for the treatment of COVID-19. The potential of 3CLpro-inhibitors to select for drug-resistant variants needs to be established. Therefore SARS-CoV-2 was passaged in vitro in the presence of increasing concentrations of ALG-097161, a probe compound designed in the context of a 3CLpro drug discovery program. We identified a combination of amino acid substitutions in 3CLpro (L50F E166A L167F) that is associated with > 20x increase in EC50 values for ALG-097161, nirmatrelvir (PF-07321332) and PF-00835231. While two of the single substitutions (E166A and L167F) provide low-level resistance to the inhibitors in a biochemical assay, the triple mutant results in the highest levels of resistance (6- to 72-fold). All substitutions are associated with a significant loss of enzymatic 3CLpro activity, suggesting a reduction in viral fitness. Structural biology analysis indicates that the different substitutions reduce the number of inhibitor/enzyme interactions while the binding of the substrate is maintained. These observations will be important for the interpretation of resistance development to 3CLpro inhibitors in the clinical setting.

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Section: Introductionmentioning

confidence: 99%

The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir

Jochmans

Liu²,

Donckers

et al. 2022

Preprint

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“…As of today, nucleoside analogs were widely used in the late 1990s for the treatment of HIV infection [51,52]. In this context, five nucleosides were initially tested as potential lethal mutagenesis agents against HIV-1: 5-hydroxydeoxycytidine, O 4 -methylthymidine, O 6 methyldeoxyguanosine, 8-aminodeoxyguanosine, and 8-oxodeoxyguanosine [13].…”

Section: Mutagenic Nucleoside Increase In Mutation Frequencymentioning

confidence: 99%

“…Molnupiravir shows a very high genetic barrier to resistance and the selection of mutants conferring drug resistance has not been successful. However, learning from experience with HIV and other viruses [52,152], combination therapies should be the choice for a most efficient treatment and, in the case of COVID-19, further studies will be necessary to test the efficacy of molnupiravir combined with remdesivir (Veklury) or the protease inhibitor nirmatrelvir (Paxlovid). Future research efforts should also concentrate on finding or designing novel, more specific mutagenic agents acting on viral polymerases, suitable for combination therapies in order to avoid the selection of escape mutants.…”

Section: Future Directions and Challengesmentioning

confidence: 99%

Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity

Hassine

M’hadheb-Gharbi

Menéndez‐Arias

2022

Viruses

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In RNA viruses, a small increase in their mutation rates can be sufficient to exceed their threshold of viability. Lethal mutagenesis is a therapeutic strategy based on the use of mutagens, driving viral populations to extinction. Extinction catastrophe can be experimentally induced by promutagenic nucleosides in cell culture models. The loss of HIV infectivity has been observed after passage in 5-hydroxydeoxycytidine or 5,6-dihydro-5-aza-2′-deoxycytidine while producing a two-fold increase in the viral mutation frequency. Among approved nucleoside analogs, experiments with polioviruses and other RNA viruses suggested that ribavirin can be mutagenic, although its mechanism of action is not clear. Favipiravir and molnupiravir exert an antiviral effect through lethal mutagenesis. Both drugs are broad-spectrum antiviral agents active against RNA viruses. Favipiravir incorporates into viral RNA, affecting the G→A and C→U transition rates. Molnupiravir (a prodrug of β-d-N4-hydroxycytidine) has been recently approved for the treatment of SARS-CoV-2 infection. Its triphosphate derivative can be incorporated into viral RNA and extended by the coronavirus RNA polymerase. Incorrect base pairing and inefficient extension by the polymerase promote mutagenesis by increasing the G→A and C→U transition frequencies. Despite having remarkable antiviral action and resilience to drug resistance, carcinogenic risks and genotoxicity are important concerns limiting their extended use in antiviral therapy.

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“…Moreover, millions of people have died from the disease. Despite the success of highly active antiretroviral therapies, the rapid emergence of drug-resistant mutants has sharply limited the clinical applications of existing anti-HIV drugs, requiring an active pipeline of new antiretrovirals [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir

et al. 2022

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The activity of nucleoside and nucleotide analogs as antiviral agents requires phosphorylation by endogenous enzymes. Phosphate-substituted analogs have low bioavailability due to the presence of ionizable negatively-charged groups. To circumvent these limitations, several prodrug approaches have been proposed. Herein, we hypothesized that the conjugation or combination of the lipophilic amide bond with nucleotide-based tenofovir (TFV) (1) could improve the anti-HIV activity. During the current study, the hydroxyl group of phosphonates in TFV was conjugated with the amino group of L-alanine, L-leucine, L-valine, and glycine amino acids and other long fatty ester hydrocarbon chains to synthesize 43 derivatives. Several classes of derivatives were synthesized. The synthesized compounds were characterized by 1H NMR, IR, UV, and mass spectrometry. In addition, several of the synthesized compounds were evaluated as racemic mixtures for anti-HIV activity in vitro in a single round infection assay using TZM-bl cells at 100 ng/mL. TFV (1) was used as a positive control and inhibited HIV infection by 35%. Among all the evaluated compounds, the disubstituted heptanolyl ester alanine phosphonamidate with naphthol oleate (69), pentanolyl ester alanine phosphonamidate with phenol oleate (62), and butanolyl ester alanine phosphonamidate with naphthol oleate (87) ester conjugates of TFV were more potent than parent drug TFV with 79.0%, 76.5%, 71.5% inhibition, respectively, at 100 ng/mL. Furthermore, two fatty acyl amide conjugates of tenofovir alafenamide (TAF) were synthesized and evaluated for comparative studies with TAF and TFV conjugates. Tetradecanoyl TAF conjugate 95 inhibited HIV infection by 99.6% at 100 ng/mL and showed comparable activity to TAF (97–99% inhibition) at 10–100 ng/mL but was more potent than TAF when compared at molar concentration.

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Update and latest advances in antiretroviral therapy

Cited by 117 publications

References 81 publications

The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir

The substitutions L50F, E166A and L167F in SARS-CoV-2 3CLpro are selected by a protease inhibitorin vitroand confer resistance to nirmatrelvir

Lethal Mutagenesis of RNA Viruses and Approved Drugs with Antiviral Mutagenic Activity

Synthesis and Evaluation of Anti-HIV Activity of Mono- and Di-Substituted Phosphonamidate Conjugates of Tenofovir

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