RdRp inhibitors and COVID-19: Is molnupiravir a good option?

Abstract

Rapid changes in the viral genome allow viruses to evade threats posed by the host immune response or antiviral drugs, and can lead to viral persistence in the host cells. RNA-dependent RNA polymerase (RdRp) is an essential enzyme in RNA viruses, which is involved in RNA synthesis through the formation of phosphodiester bonds. Therefore, in RNA viral infections such as SARS-CoV-2, RdRp could be a crucial therapeutic target. The present review discusses the promising application of RdRp inhibitors, previously approved or currently being tested in human clinical trials, in the treatment of RNA virus infections. Nucleoside inhibitors (NIs) bind to the active site of RdRp, while nonnucleoside inhibitors (NNIs) bind to allosteric sites. Given the absence of highly effective drugs for the treatment of COVID-19, the discovery of an efficient treatment for this pandemic is an urgent concern for researchers around the world. We review the evidence for molnupiravir (MK-4482, EIDD-2801), an antiviral drug originally designed for Alphavirus infections, as a potential preventive and therapeutic agent for the management of COVID-19. At the beginning of this pandemic, molnupiravir was in preclinical development for seasonal influenza. When COVID-19 spread dramatically, the timeline for development was accelerated to focus on the treatment of this pandemic. Real time consultation with regulators took place to expedite this program. We summarize the therapeutic potential of RdRp inhibitors, and highlight molnupiravir as a new small molecule drug for COVID-19 treatment.

The Role of Cytokines and Chemokines in Severe Acute Respiratory Syndrome Coronavirus 2 Infections

“…Paxlovid, a ritonavir-boosted protease inhibitor, is the first oral antiviral drug to receive FDA granted EUA in December of 2021 ( 41 ). Both remdesivir ( 60 ) and molnupiravir ( 61 , 62 ) can inhibit viral replication by inhibiting RNA-dependent RNA polymerase (RdRp) ( 60 – 64 ).…”

Computational Analysis of Molnupiravir

“…Thus, two acidic protons of the N 4 -hydroxylcytosine fragment are of great importance and play a pivotal role in a rich library of plausible tautomeric forms of molnupiravir. Notably, to the best of our knowledge, the The dire need to search for antiviral agents to combat COVID-19 has led to the emergence of studies on the effectiveness of molnupiravir against SARS-CoV-2 [9][10][11][12][13][14][15][16]. As of October 2021, it was established that oral administration of molnupiravir reduces the risk of severe disease by about 50% in comparison to placebo in patients with mild to moderate disease.…”

SARS-CoV-2 and Coronavirus Disease Mitigation: Treatment Options, Vaccinations and Variants

“…Additionally, there was no effect of SARS-CoV-2 variants, symptoms onset time, or patients' risk factors on the efficacy of molnupiravir [125]. Molnupiravir can also effectively decrease the nasopharyngeal SARS-CoV-2 virus and viral RNA isolation at day 3 and no virus was isolated at day 5 of administration [126,127].…”

“…Molnupiravir is an oral antiviral that has activity like Remdesivir and favipiravir. It can effectively inhibit the RNA-dependent RNA polymerase of viruses such as influenza and alphavirus infections [124][125][126]. Accordingly, the utility of molnupiravir in COVID-19 treatment is being evaluated by several researchers.…”