Molnupiravir and Its Antiviral Activity Against COVID-19

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) constitutes a major worldwide public health threat and economic burden. The pandemic is still ongoing and the SARS-CoV-2 variants are still emerging constantly, resulting in an urgent demand for new drugs to treat this disease. Molnupiravir, a biological prodrug of NHC (β-D-N(4)-hydroxycytidine), is a novel nucleoside analogue with a broad-spectrum antiviral activity against SARS-CoV, SARS-CoV-2, Middle East respiratory syndrome coronavirus (MERS-CoV), influenza virus, respiratory syncytial virus (RSV), bovine viral diarrhea virus (BVDV), hepatitis C virus (HCV) and Ebola virus (EBOV). Molnupiravir showed potent therapeutic and prophylactic activity against multiple coronaviruses including SARS-CoV-2, SARS-CoV, and MERS-CoV in animal models. In clinical trials, molnupiravir showed beneficial effects for mild to moderate COVID-19 patients with a favorable safety profile. The oral bioavailability and potent antiviral activity of molnupiravir highlight its potential utility as a therapeutic candidate against COVID-19. This review presents the research progress of molnupiravir starting with its discovery and synthesis, broad-spectrum antiviral effects, and antiviral mechanism. In addition, the preclinical studies, antiviral resistance, clinical trials, safety, and drug tolerability of molnupiravir are also summarized and discussed, aiming to expand our knowledge on molnupiravir and better deal with the COVID-19 epidemic.

Keywords: COVID-19; SARS-CoV-2; antiviral; molnupiravir; orally bioavailable; safety.

Figure 1

The chemical structures of Molnupiravir, NHC and EIDD-1931-triphopsphate. (A) Molnupiravir, Beta-D-N4-hydroxycytidine-5’-isopropyl ester (MK-4482/EIDD-2801) is a bioactive prodrug of NHC (EIDD-1931). (B) Beta-D-N4-hydroxycytidine(NHC,EIDD-1931) is an orally bioavailable ribonucleoside analogue, which has broad-spectrum activity against a variety of RNA viruses. (C) EIDD-triphosphate can be used as a competitive alternative substrate for viral RNA-dependent RNA polymerase (RdRp), integrates into viral RNA and leads to the accumulation of mutations in the viral genome, resulting in lethal mutations.

Figure 2

The research history of molnupiravir. Molnupiravir is a prodrug of the ribonucleoside analog β-D-N4-hydroxycytidine (NHC), which has multi-antiviral activities against various viruses including HCV, SARS-CoV, HBV and so on, given the pharmacological mechanism is inducing mutagenesis of viral DNA or RNA.

Figure 3

A schematic illustration of the mechanism of molnupiravir and remdesivir. (A) NHC monophosphate (M) can bind to A or G. (B) NHC triphosphate can be used as a substrate for RNA synthesis, the addition of NHC monophosphate (M) does not terminate the extension of anti-sense RNA chain but induces accumulating mutations. (C) The active form of remdesivir acts as a nucleoside analog, remdesivir triphosphate (RTP) can be used as a substrate and the remdesivir monophosphate (R) can pair with uridine monophosphate (U) in the RNA template strand. The addition of the fourth nucleotide following remdesivir is terminated because of a translocation barrier, thus the RNA replication will be impacted.

Figure 4

A schematic illustration of the mechanisms of developed anti-SARS-CoV-2 drugs. Anti-SARS-CoV-2 drugs can be classified into 4 main classes according to their different action mechanisms, class 1 drugs include Cepharanthine, HCQ, Arbidol, Camostat mesylate, and S protein targeted-antibodies including Bamlanivimab and Sotrovimab, which can prevent the entry of SARS-CoV-2; class 2 drugs include Ribavirin, Favipiravir, Remdesivir and Molnupiravir, which can inhibit the viral RNA synthesis; class 3 drugs include Lopinavir/Ritonavir and Paxlovid, which can inhibit viral 3CL protease; and class 4 drugs mainly include Tocilizumab and other inflammatory-alleviated drugs.