Antiviral Nucleoside and Nucleotide Analogs: A Review

Mahmoud, Sawsan A.; Hasabelnaby, Sherifa; Hammad, Sherif F.; Sakr, Tamer M.

doi:10.21608/aprh.2018.5829

Cited by 39 publications

(34 citation statements)

References 67 publications

(55 reference statements)

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“…Inhibition by nucleoside analogues can be accomplished through a variety of mechanisms. Common mechanisms of action include incorporation of the analogue by the viral polymerase to induce premature termination of strand synthesis and loss of essential genetic information through mutagenesis (22)(23)(24)(25). A previous study reported that the nucleoside analogues ribavirin (RBV) and 5-fluorouracil (5-FU) did not potently inhibit CoVs, and this finding was attributed to the proofreading capabilities of the viral 3=-5= exoribonuclease (ExoN) (26).…”

mentioning

confidence: 99%

Small-Molecule Antiviral β- d - N ⁴ -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

Agostini

Pruijssers

Chappell

et al. 2019

J Virol

288

281

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Coronaviruses (CoVs) have emerged from animal reservoirs to cause severe and lethal disease in humans, but there are currently no FDA-approved antivirals to treat the infections. One class of antiviral compounds, nucleoside analogues, mimics naturally occurring nucleosides to inhibit viral replication. While these compounds have been successful therapeutics for several viral infections, mutagenic nucleoside analogues, such as ribavirin and 5-fluorouracil, have been ineffective at inhibiting CoVs. This has been attributed to the proofreading activity of the viral 3=-5= exoribonuclease (ExoN). ␤-D-N 4 -Hydroxycytidine (NHC) (EIDD-1931; Emory Institute for Drug Development) has recently been reported to inhibit multiple viruses. Here, we demonstrate that NHC inhibits both murine hepatitis virus (MHV) (50% effective concentration [EC 50 ] ϭ 0.17 M) and Middle East respiratory syndrome CoV (MERS-CoV) (EC 50 ϭ 0.56 M) with minimal cytotoxicity. NHC inhibited MHV lacking ExoN proofreading activity similarly to wild-type (WT) MHV, suggesting an ability to evade or overcome ExoN activity. NHC inhibited MHV only when added early during infection, decreased viral specific infectivity, and increased the number and proportion of G:A and C:U transition mutations present after a single infection. Low-level NHC resistance was difficult to achieve and was associated with multiple transition mutations across the genome in both MHV and MERS-CoV. These results point to a virusmutagenic mechanism of NHC inhibition in CoVs and indicate a high genetic barrier to NHC resistance. Together, the data support further development of NHC for treatment of CoVs and suggest a novel mechanism of NHC interaction with the CoV replication complex that may shed light on critical aspects of replication. IMPORTANCE The emergence of coronaviruses (CoVs) into human populations from animal reservoirs has demonstrated their epidemic capability, pandemic potential, and ability to cause severe disease. However, no antivirals have been approved to treat these infections. Here, we demonstrate the potent antiviral activity of a broadspectrum ribonucleoside analogue, ␤-D-N 4 -hydroxycytidine (NHC), against two divergent CoVs. Viral proofreading activity does not markedly impact sensitivity to NHC inhibition, suggesting a novel interaction between a nucleoside analogue inhibitor and the CoV replicase. Further, passage in the presence of NHC generates only lowlevel resistance, likely due to the accumulation of multiple potentially deleterious transition mutations. Together, these data support a mutagenic mechanism of inhibition by NHC and further support the development of NHC for treatment of CoV infections. FIG 2 NHC inhibits MHV and MERS-CoV with minimal cytotoxicity. (A and B) Changes in MHV (A) and MERS-CoV (B) titers relative to vehicle control after treatment with increasing concentrations of NHC. The data represent the results of 6 independent experiments, each with 3 replicates. The error bars represent standard errors of the mean (SEM). (C) Changes in ti...

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mentioning

confidence: 99%

Small-Molecule Antiviral β- d - N ⁴ -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

Agostini

Pruijssers

Chappell

et al. 2019

J Virol

288

281

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“…Viral antagonists are promising drug targets for the development of novel antiviral therapies. Many current antiviral therapies are based on nucleoside analogues (NA) [ 133 ]. NAs highly resemble their cellular dNTP counterparts, but lead to a premature termination of DNA synthesis, when incorporated into the viral genome as substrates for RTs and DNA polymerases.…”

Section: Discussionmentioning

confidence: 99%

SAMHD1 … and Viral Ways around It

Deutschmann

Gramberg

2021

Viruses

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The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays a crucial role for a variety of different cellular functions. Besides balancing intracellular dNTP concentrations, facilitating DNA damage repair, and dampening excessive immune responses, SAMHD1 has been shown to act as a major restriction factor against various virus species. In addition to its well-described activity against retroviruses such as HIV-1, SAMHD1 has been identified to reduce the infectivity of different DNA viruses such as the herpesviruses CMV and EBV, the poxvirus VACV, or the hepadnavirus HBV. While some viruses are efficiently restricted by SAMHD1, others have developed evasion mechanisms that antagonize the antiviral activity of SAMHD1. Within this review, we summarize the different cellular functions of SAMHD1 and highlight the countermeasures viruses have evolved to neutralize the restriction factor SAMHD1.

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“…The simulated structure may then be incorporated into the virus; and in this sense may be considered a "counterfeit" agent-with therapeutic benefit. 20 Remdesivir works when the enzyme replicating the genetic material for the novel coronavirus-RNA polymerase-incorporates the adenosine analogue in place of the natural molecule into the growing RNA strand. By introduction of the modified agent remdesivir, replication of the novel coronavirus is interrupted, and the virus ceases to multiply and is not able to infect more cells in the body.…”

Section: How Does Remdesivir Work?mentioning

confidence: 99%

Remdesivir and Coronavirus Disease 2019 (COVID-19): Essential Questions and Answers for Pharmacists and Pharmacy Technicians

Veronin

Lang

Reinert

2020

Journal of Pharmacy Technology

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Objective: To conduct a review of the investigational drug remdesivir and its therapeutic potential for treatment of COVID-19, in the form of a series of questions and answers. The purpose of the review is to narrow gaps in knowledge, clarify concepts, and to investigate research advancements for health care professionals. Data Sources: From June 2020 to August 2020, we conducted comprehensive searches of MEDLINE-PubMed, Scopus, and Google Scholar databases with no time limitations. Search terms were included that contained the terms “remdesivir,” “COVID-19,” “novel coronavirus” and “evidence,” “therapy,” “safety,” “effectiveness,” “efficacy,” “clinical trial.” Study Selection and Data Extraction: The sources of information include all publicly available data from previously published research reports. Reports must have at least one reference to remdesivir as a treatment modality for COVID-19 with no specified outcomes. Data Synthesis: Major research findings on the efficacy and safety of remdesivir are summarized in tabular format and presented in chronological order. Results of this review reveal remdesivir to be an effective therapy in specific clinical contexts; however, in several areas, available data are insufficient to support evidence-based guidance for remdesivir in the treatment of COVID-19. Conclusions: Clinical trials on remdesivir are ongoing, yet questions remain and further research is needed as to the selection of patients, effectiveness, and duration of treatment in the use of remdesivir for treatment of COVID-19.

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Antiviral Nucleoside and Nucleotide Analogs: A Review

Cited by 39 publications

References 67 publications

Small-Molecule Antiviral β- d - N ⁴ -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

Small-Molecule Antiviral β- d - N ⁴ -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

SAMHD1 … and Viral Ways around It

Remdesivir and Coronavirus Disease 2019 (COVID-19): Essential Questions and Answers for Pharmacists and Pharmacy Technicians

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Antiviral Nucleoside and Nucleotide Analogs: A Review

Cited by 39 publications

References 67 publications

Small-Molecule Antiviral β- d - N 4 -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

Small-Molecule Antiviral β- d - N 4 -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

SAMHD1 … and Viral Ways around It

Remdesivir and Coronavirus Disease 2019 (COVID-19): Essential Questions and Answers for Pharmacists and Pharmacy Technicians

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Product

Resources

About

Small-Molecule Antiviral β- d - N ⁴ -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance

Small-Molecule Antiviral β- d - N ⁴ -Hydroxycytidine Inhibits a Proofreading-Intact Coronavirus with a High Genetic Barrier to Resistance