Repurposing Molnupiravir for COVID-19: The Mechanisms of Antiviral Activity

Yip, Ashley Jia Wen; Low, Zheng Yao; Chow, Vincent T. K.; Lal, Sunil K.

doi:10.3390/v14061345

Cited by 35 publications

(25 citation statements)

References 81 publications

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“… Here, the high structural similarity of molnupiravir triphosphate to nucleotide triphosphates (especially CTP) causes SARS-CoV-2 RdRp to mistakenly insert it into the genome of new virions. This eventually causes the accumulation of inactivating mutations, so the replication of the virus is disrupted …”

Section: Anti-covid-19 Drugsmentioning

confidence: 99%

An Overview on Anti-COVID-19 Drug Achievements and Challenges Ahead

Valipour,

Irannejad,

Keyvani

2023

ACS Pharmacol. Transl. Sci.

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The appearance of several coronavirus pandemics/ epidemics during the last two decades (SARS-CoV-1 in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019) indicates that humanity will face increasing challenges from coronaviruses in the future. The emergence of new strains with similar transmission characteristics as SARS-CoV-2 and mortality rates similar to SARS-CoV-1 (∼10% mortality) or MERS-CoV (∼35% mortality) in the future is a terrifying possibility. Therefore, getting enough preparations to face such risks is an inevitable necessity. The present study aims to review the drug achievements and challenges in the fight against SARS-CoV-2 with a combined perspective derived from pharmacology, pharmacotherapy, and medicinal chemistry insights. Appreciating all the efforts made during the past few years, there is strong evidence that the desired results have not yet been achieved and research in this area should still be pursued seriously. By expressing some pessimistic possibilities and concluding that the drug discovery and pharmacotherapy of COVID-19 have not been successful so far, this short essay tries to draw the attention of responsible authorities to be more prepared against future coronavirus epidemics/pandemics.

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Section: Anti-covid-19 Drugsmentioning

confidence: 99%

An Overview on Anti-COVID-19 Drug Achievements and Challenges Ahead

Valipour,

Irannejad,

Keyvani

2023

ACS Pharmacol. Transl. Sci.

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“…Its active form, β-D-N4-hydroxycytidine triphosphate (NHC-TP) is preferentially used as substrate by SARS-CoV-2 RdRp, and incorporated instead of cytidine or uridine into the newly synthesized viral RNA. Compared to remdesivir, which terminates viral synthesis, molnupiravir allows the continuation of the process, but the resultant RNA template contains multiple mutations, with interconversions of cytidine to uridine and guanosine to adenosine, which cumulate to constitute catastrophic errors in the new virions, leading to formation of non-functional viruses (Yip et al, 2022;Streinu-Cercel et al, 2022a).…”

Section: Molnupiravirmentioning

confidence: 99%

Therapeutic developments for SARS-CoV-2 infection—Molecular mechanisms of action of antivirals and strategies for mitigating resistance in emerging variants in clinical practice

et al. 2023

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This article systematically presents the current clinically significant therapeutic developments for the treatment of COVID-19 by providing an in-depth review of molecular mechanisms of action for SARS-CoV-2 antivirals and critically analyzing the potential targets that may allow the selection of resistant viral variants. Two main categories of agents can display antiviral activity: direct-acting antivirals, which act by inhibiting viral enzymes, and host-directed antivirals, which target host cell factors that are involved in steps of the viral life cycle. We discuss both these types of antivirals, highlighting the agents that have already been approved for treatment of COVID-19, and providing an overview of the main molecules that are currently in drug development. Direct-acting antivirals target viral enzymes that are essential in the viral life cycle. Three direct-acting antivirals are currently in use: two are nucleoside analogs that inhibit the RNA-dependent RNA polymerase of SARS-CoV-2, i.e., remdesivir and molnupiravir, and the third one, nirmatrelvir/ritonavir, is an inhibitor of SARS-CoV-2 main protease. The potential for induction of viral resistance is discussed for each of these antivirals, along with their clinical activity on each of the SARS-CoV-2 variants and sublineages that have been dominant over the course of the pandemic, i.e., Alpha, Delta, as well as Omicron and its sublineages BA.1, BA.2, BA.5, BQ.1 and XBB. Host-directed antivirals are currently in preclinical or clinical development; these agents target host cell enzymes that are involved in facilitating viral entry, replication, or virion release. By blocking these enzymes, viral replication can theoretically be effectively stopped. As no SARS-CoV-2 host-directed antiviral has been approved so far, further research is still needed and we present the host-directed antivirals that are currently in the pipeline. Another specific type of agents that have been used in the treatment of COVID-19 are neutralizing antibodies (NAbs). Their main binding site is the spike protein, and therefore their neutralization activity is influenced by mutations occurring in this region. We discuss the main changes in neutralization activity of NAbs for the most important dominant SARS-CoV-2 variants. Close monitoring of emerging variants and sublineages is still warranted, to better understand the impact of viral mutations on the clinical efficiency of antivirals and neutralizing antibodies developed for the treatment of COVID-19.

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“…It has a broad-spectrum antiviral activity against RNA viruses like influenza, SARS, MERS, and Ebola. Due to this, it was repurposed to be used against mild-to-moderate COVID-19 cases [12,13]. It's a nucleoside analog that targets the RNA-dependent RNA-polymerase (RdRp) enzyme, which lies in the core of coronaviruses replication machinery [14], inducing errors in the RNA sequence, producing a fatally mutated viral RNA, and even inhibiting the RdRp enzyme.…”

Section: Molnupiravirmentioning

confidence: 99%

Review article on instrumental analysis of Molnupiravir, Favipiravir, and Ritonavir in different matrices

Saraya

salman²,

batakoushi

et al. 2023

Octahedron Drug Research

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Ever since the emergence of the COVID-19 outbreak, there have been so many casualties worldwide. According to WHO, more than half a billion people were infected by the virus, of which 6.5 million deaths were counted. However, some already existing antivirals were repositioned and repurposed as anti-COVID-19 therapeutics such as molnupiravir, favipiravir, and ritonavir. The emergency needs to develop effective anti-viral drugs for the treatment of COVID-19 infection Consequently, there arose a need for effective, rapid, accurate, and reliable techniques for the determination of these antivirals. Here in this review, the different reported analytical methods for the quantitative determination of the studied anti-viral drugs were discussed. These reported methods include spectrophotometric methods, spectroflurometric methods, electrochemical methods, and different chromatographic methods, wither the reported method used for the quantitative determination of the studied anti-viral drugs in a single dosage form or in a co-formulated mixture also in different biological fluids and samples.

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Repurposing Molnupiravir for COVID-19: The Mechanisms of Antiviral Activity

Cited by 35 publications

References 81 publications

An Overview on Anti-COVID-19 Drug Achievements and Challenges Ahead

An Overview on Anti-COVID-19 Drug Achievements and Challenges Ahead

Therapeutic developments for SARS-CoV-2 infection—Molecular mechanisms of action of antivirals and strategies for mitigating resistance in emerging variants in clinical practice

Review article on instrumental analysis of Molnupiravir, Favipiravir, and Ritonavir in different matrices

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