Molnupiravir

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Cat Number

API2349386894

CAS Number

2349386-89-4

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CAS Number

2349386-89-4

EINECS

604-604-1

Storage

Store at -20 ℃

Synonyms

((2R,3S,4R,5R)-3,4-dihydroxy-5-((E)-4-(hydroxyimino)-2-oxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate; EIDD-2801; Uridine, 4-oxime, 5'-(2-methylpropanoate); β-D-N4 hydroxycytidine-5'-isopropyl ester

Molecular Formula

C13H19N3O7

Molecular Weight

329.31

Smiles

CC(C)C(=O)OC[C@@H]1[C@H]([C@H]([C@@H](O1)N2C=CC(=NC2=O)NO)O)O

Melting Point

156 - 159 ℃

General Description

Molnupiravir is an oral antiviral prodrug prescribed, demonstrates broad-spectrum antiviral activity against multiple RNA viruses beyond its primary use for SARS-CoV-2. It is effective against chikungunya virus, hepatitis C virus, influenza viruses, Ebola virus, and other coronaviruses including SARS-CoV-1.

Mechanism of Action

Molnupiravir is a prodrug of N-hydroxycytidine (NHC), which is then metabolized into its triphosphate form (NHC-TP) intracellularly. NHC-TP is a competitive substrate of viral RNA-dependent RNA polymerase (RdRp). NHC, present as NHC-TP, is incorporated into the nascent viral RNA (vRNA) chain during replication. Due to tautomerization of NHC, it is able to mispair with guanosine and adenosine, leading to antiparallel base pairing (G→A and C→U transitions). This "viral error catastrophe" mechanism introduces numerous mutations into the viral genome beyond a viable threshold. The accumulation of lethal mutations in subsequent replication cycles renders the virus noninfectious, without terminating RNA chain elongation.

Application

Molnupiravir, initially developed for influenza treatment, received Emergency Use Authorization (EUA) from the FDA on December 23, 2021. This authorization permits its use in treating adults with mild to moderate COVID-19 who are at high risk for severe illness, provided treatment begins within 5 days of symptom onset, and alternative antiviral options are not clinically appropriate.

As a prodrug of NHC, molnupiravir is first converted to NHC in cells, and then phosphorylated to its active metabolite, NHC-TP, which is subsequently incorporated into viral RNA by RdRp, without chain termination. NHC-TP's tautomerization results in ambiguous base pairing (C/U-like), leading to cumulative mutations in viral RNA replication. Accumulation of mutations above the error threshold can lead to an error catastrophe, rendering the virus noninfectious.
Molnupiravir's error catastrophe mechanism has been demonstrated using SARS-CoV-2 in vitro, where the drug induces high levels of viral mutation and reduced viral infectivity. Molnupiravir has sub- to low-micromolar EC50 against SARS-CoV-1, MERS-CoV, and SARS-CoV-2 in cells, and unlike antibodies that target the spike protein of SARS-CoV-2, its RdRp-targeting mechanism of action has proven active against all known SARS-CoV-2 variants (alpha to omicron) so far, with relatively little variation in IC50 (0.28–5.5 μM), generally within a twofold range of the wild-type strain.

Fig. 1 Molnupiravir works by a novel mechanism known as viral error induction. (Maas, BM.; et al. 2024)

References

Maas, BM, et al. Molnupiravir: Mechanism of action, clinical, and translational science.Clinical and Translational Science, 2024, 17(2): e13732.

COVID-19 is a disease caused by the SARS-CoV-2 virus that has led to a high mortality and morbidity rate worldwide since 2019. Molnupiravir (MOL) is a nucleoside prodrug that is biologically activated by two metabolites to prevent viral proliferation through RdRp, Mpro, and spike protein inhibition and is able to decrease hospitalization and mortality rates in patients with COVID-19.
Thirumalaisamy R et al. synthesized a hyaluronic acid conjugate of molnupiravir (HA-MOL) to optimize drug delivery by exploiting the polymer's binding ability to CD44, which is overexpressed in cancer cells and inflamed sites. The HA-MOL conjugate will enter the host cell through CD44-mediated endocytosis that is different from SARS-CoV-2's cell entry pathway (via ACE2), where an ester bond on the polymer conjugate is cleaved by lysosomal enzymes, which in turn releases MOL into the intracellular site. The drug, upon cell entry, can block viral replication and translation processes. In addition, glycosylation and the autophagosome trigger lysosomal degradation of the virus's envelope, genetic material, and other constituents as a way to facilitate the clearance of the virus. The method in which MOL is administered will reduce its toxicity on non-targeted areas of the body and prevent the spread of COVID-19.

Fig. 2 Key Biological Steps involved in cell targeted drug delivery (CTDD) pattern of HA-MOL conjugate. (Thirumalaisamy R.; et al. 2025)

References

Thirumalaisamy R, et al. Molecular insights of hyaluronic acid-molnupiravir conjugate as a new drug in targeting SARS-CoV-2 viral proteins. International journal of advanced Science and Engineering, 2025, 11(3): 4175-4195.