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.

Keywords: Clinical trials; RdRp inhibitors, Molnupiravir; SARS-CoV-2; Small molecule drug.

Fig. 1

Schematic representation of the structure and genome of coronavirus (A) and the replication cycle of SARS-CoV-2 (B). The structural proteins of the virus include proteins S, E, M, and N. Coronaviruses are approximately 100–160 nm in diameter, and enveloped with a lipid bilayer. This virus family has a large genome (positive-sense single-stranded RNA about 30 Kb length) that is bound to the nucleocapsid. The S proteins consist of subunits S1 and S2 and also TMPRSS2 and furin-related cleavage locations. S proteins are responsible for host cell-virus attachment following TMPRSS2-mediated activation. The S protein structure in the pre-fusion conformation, and genome plus C-terminal domain crystal structure of S protein combined with human ACE2 are shown in (A). The stages of coronavirus life cycle include (B) attachment and penetration (1), uncoating (2), gene expression (3 and 5–6) and replication (4), assembly (7−8), and release (9).

Fig. 2

Schematic view of SARS-CoV-2 replication and infection in host cells and possible therapeutic approaches through interfering with the replication cycle of SARS-CoV-2. This virus binds to the ACE2 receptor of host cells, followed by endocytosis, uncoating, replication by host cell machinery to form new viral components and eventually the release of virions via exocytosis. These processes could be impeded during any step through drug repurposing (highlighted in red). The virus triggers host immunity to express cytokines and inflammatory responses, and causes immune dysfunction by inducing or hindering different immune cells like neutrophils, macrophages, NK cells and dendritic cells, leading to multiple organ failure, septic shock, sepsis and even mortality. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)

Fig. 3

Possible mechanism of cytokine storm development by SARS-CoV-2. There is an association between COVID-19 and elevated level of cytokines such as IL-6, TNF-α and IL-10. ISGs, IFN-triggered genes.

Fig. 4

Mechanism of action of antiviral effects of favipiravir (T-705). After incorporation into the cell, the drug is converted to favipiravir ribofuranosyl-5′-triphosphate (T-705-RTP) in the host cells. Favipiravir enters the purine nucleotide salvage pathways via purine phosphoribosyltransferase, and is then converted to favipiravir-triphosphate after phosphorylation by viral RNA-dependent RNA polymerase (RdRp). Hypoxanthine guanine phosphoribosyltransferase plays a role in favipiravir phosphorylation. T-705-RTP competes with purine nucleosides to be integrated into the virus RNA, and thus interferes with virus replication, by inhibiting the RdRp present in the RNA virus .

Fig. 5

Mulnopiravir is transformed to EIDD-1931 (NHC) rapidly in plasma, and then to active antiviral agent of EIDD-1931 5′-triphosphate following dispersion in different tissues through host kinases.

Fig. 6

NHC model of mutagenesis versus SARS-CoV-2; (A) Schematic incorporation of nucleotide into RNA primer (gray circles) or template (white circles) mediated by RNA-dependent RNA polymerase (oval) of SARS-CoV-2; minus and plus marks indicate RNA sense; U, G, C and A letters are natural nucleotide bases and M letter is molnupiravir; NTP triphosphate moiety is three small circles; (B) Tautomerization accounts for alternative base-pairing of NHC base moiety. N-hydroxylamine is predominant tautomer in the presence of NHC-TP substrate, but oxime and N-hydroxylamine forms are both found in the presence of template-embedded NHC-MP.; (C) Mechanism of template-embedded NHC-MP action for viral mutagenesis and inhibition. Incorporation of NTP into template NHC-MP is shown as blue circles.; (D) Mutagenic and inhibitory effects of NHC on viral replication. (For interpretation of the references to colour in this figure, the reader is referred to the web version of this article.)