key: cord-0693725-an3ki4yo authors: Pourkarim, Fariba; Pourtaghi‐Anvarian, Samira; Rezaee, Haleh title: Molnupiravir: A new candidate for COVID‐19 treatment date: 2021-12-30 journal: Pharmacol Res Perspect DOI: 10.1002/prp2.909 sha: 9a0d9155fe158b29bad2121d6f2157fb061e1c9d doc_id: 693725 cord_uid: an3ki4yo The novel coronavirus disease 2019 (COVID‐19) emerged in late December 2019 in china and has rapidly spread to many countries around the world. The effective pharmacotherapy can reduce the mortality of COVID‐19. Antiviral medications are the candidate therapies for the management of COVID‐19. Molnupiravir is an antiviral drug with anti‐RNA polymerase activity and currently is under investigation for the treatment of patients with COVID‐19. This review focuses on summarizing published literature for the mechanism of action, safety, efficacy, and clinical trials of molnupiravir in the treatment of COVID‐19 patients. preferred for patients due to its ease of use. The RNA-dependent RNA polymerase (RdRp) is a key enzyme for the replication of SARS-CoV-2 and plays a central role in the pathophysiology of COVID-19. 16 Molnupiravir (EIDD-2801, MK-4482), an oral ribonucleoside analog with broad-spectrum antiviral activity, is an isopropyl ester prodrug of ′Β-D-N4-hydroxycytidine (known, EIDD-1931 or NHC) and targets RdRp. 17 It blocks the SARS-CoV-2 replication in cell lines, animal infected models, and culture media containing airway epithelial cells [18] [19] [20] and has been suggested as a candidate treatment for COVID-19. 16 One of the advantages of this drug target is that the RNA-dependent polymerase has no equivalent in the human. This drug is currently under review by the United States Food and Drug Administration. We aimed to review the clinical evidence about the safety and efficacy of the molnupiravir administration in the treatment of patients with COVID-19. Coronaviruses (CoVs) have four main structural proteins, including spike, membrane, envelope, and nucleocapsid proteins. CoVs enter the host cell through the interaction between the spike protein and the host cell receptors such as angiotensin-converting enzyme 2 and CD147. [21] [22] [23] RdRp is responsible for the CoVs replication in host cells which leads to the production of CoVs with high mutagenicity and diversity. 24 After initial exposure, the immune system is triggered via cytotoxic cells, antibodies, and interferons. In the advanced stages of COVID-19, the alveolar infiltration of T cells, neutrophils, and macrophages contribute to cytokine production such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha. Cytokine storm results in acute respiratory distress syndrome (ARDS), and multi-organ dysfunction. 25 Hyperinflammatory is also associated with the hypercoagulable state via overexpression of tissue factor in the coagulation cascade. In plasma, molnupiravir is converted to the active nucleoside analog (EIDD-1931) by host esterases. EIDD-1931 26 Molnupiravir inhibits the RdRp enzyme of SARS-CoV-2, and causes several errors in the RNA virus replication. 27 In other words, molnupiravir-like remdesivir can reduce the pathogenesis and replication of coronaviruses. The results of the docking study showed that the limited space of mutations in the drug structure can cause the inhibitory effects of molnupiravir on the appearance of drug resistance-related mutations. Therefore, molnupiravir can be effective in treating patients with resistance to remdesivir. 28 Based on pharmacokinetic studies, molnupiravir should be administered twice daily to provide an adequate concentration in the respiratory tissues. 17 Based on the results of clinical trials, molnupiravir is well absorbed orally and shows linear pharmacokinetics between doses of 50-1600 mg. Administration of molnupiravir with food may significantly decrease the rate of absorption. However, the extent of absorption is similar in both with or without food. Therefore, the administration of molnupiravir with food is conflicting. 29 Headache, nausea, and diarrhea are the most common adverse effects of molnupiravir. Other adverse effects include influenza-like syndrome, back pain, rhinorrhea, hot flashes, and pain in extremity. 29, 30 Trace amounts of molnupiravir found in the urine. 29 Molnupiravir is a mutagenic nucleotide analog that causes mutagenesis in the DNA of mammalian cells. Theoretically increases concerns about its interference with vaccination. Furthermore, that leads to potential carcinogenic and teratogenic effects on sperm precursors and embryonic growth. However, in the suggested dose, twice a day for 5 days is not commonly possible. 31, 32 There are no comprehensive studies describing its metabolism in the body, blood carriers, and drug-drug interactions. 33 Indeed, no identified interaction with transporters, liver enzymes, and other drugs have been reported even by its active metabolite. 33, 34 Therefore, more studies are needed to clarify the metabolism and drug-drug interactions of molnupiravir. Due to the potential of molnupiravir for teratogenicity, it should not be used during pregnancy until further studies clarify their teratogenicity risk. 17 Several studies have investigated the inhibitory effects of molnupiravir on COVID-19 replication in animal models. In the study conducted by Wahl et al. 26 the effects of EIDD-2801 on lung infection were investigated in mice. In this study, lung-only mice 20 The details of these studies are given in Table 1 There was a reduction in the absorption rate but no decrease in overall exposure. This review article might have some limitations. First, due to the limited published data about the use of molnupiravir in COVID-19, more data are needed to support the application of molnupiravir in the treatment of COVID-19. Second, like most review articles, some studies may be missed to come into our review. The RdRp is an essential enzyme for COVID-19 replication and seems to play a key role in the pathophysiology of COVID-19. Molnupiravir targets RdRp and is a candidate drug for COVID-19 treatment. Based on animal studies, molnupiravir can be effective in COVID-19, but well-designed randomized clinical trial studies are required in the future to confirm the therapeutic effects of molnupiravir in patients with COVID-19. No ethical approval required for the review article. The authors declare that there is no conflict of interest. HR and SPA, devised the main conceptual ideas. FP, SPA, and HR, wrote the initial draft of the manuscript. FP and HR, reviewed the manuscript and edited it critically for important intellectual content. All authors read and approved the final manuscript. 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