Molnupiravir

Molnupiravir, also known as EIDD-2801 and MK-4482, is an orally bioavailable form of a highly potent ribonucleoside analog that inhibits the replication of multiple RNA viruses including SARS-CoV-2. EIDD-2801 has been shown to improve pulmonary function, decrease body weight loss and reduce the amount of virus in the lung. In addition to activity against coronaviruses, EIDD-2801, in laboratory studies, has demonstrated activity against seasonal and bird influenza, respiratory syncytial virus, chikungunya virus, Ebola virus, Venezuelan equine encephalitis virus, and Eastern equine encephalitis virus. EIDD-2801 is a prodrug of EIDD-1931.

Product information

CAS Number: 2349386-89-4

Molecular Weight: 329.31

Formula: C13H19N3O7

Synonym:

EIDD-2801

MK4482

Chemical Name: ((2R, 3S, 4R, 5R)-3, 4-dihydroxy-5-((E)-4-(hydroxyimino)-2-oxo-3, 4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methyl isobutyrate

Smiles: CC(C)C(=O)OC[C@H]1O[C@H]([C@H](O)[C@@H]1O)N1C=C/C(/NC1=O)=N\O

InChiKey: HTNPEHXGEKVIHG-QCNRFFRDSA-N

InChi: InChI=1S/C13H19N3O7/c1-6(2)12(19)22-5-7-9(17)10(18)11(23-7)16-4-3-8(15-21)14-13(16)20/h3-4,6-7,9-11,17-18,21H,5H2,1-2H3,(H,14,15,20)/t7-,9-,10-,11-/m1/s1

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: DMSO: 100 mg/mL (303.67 mM)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥12 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

Molnupiravir is a broad-spectrum antiviral that is an orally bioavailable prodrug of the nucleoside analogue β-D-N4-hydroxycytidine (NHC). Molnupiravir or NHC can increase G to A and C to U transition mutations in replicating coronaviruses. These increases in mutation frequencies can be linked to increases in antiviral effects. Here, the effects of the active compound NHC 5'-triphosphate (NHC-TP) against the purified severe acute respiratory syndrome coronavirus 2 RNA-dependent RNA polymerase complex were studied. The efficiency of incorporation of natural nucleotides over the efficiency of incorporation of NHC-TP into model RNA substrates followed the order GTP (12, 841) > ATP (424) > UTP (171) > CTP (30), indicating that NHC-TP competes predominantly with CTP for incorporation. No significant inhibition of RNA synthesis was noted as a result of the incorporated monophosphate in the RNA primer strand. When embedded in the template strand, NHC-monophosphate supported the formation of both NHC:G and NHC:A base pairs with similar efficiencies. The extension of the NHC:G product was modestly inhibited, but higher nucleotide concentrations could overcome this blockage. In contrast, the NHC:A base pair led to the observed G to A (G:NHC:A) or C to U (C:G:NHC:A:U) mutations. Together, these biochemical data support a mechanism of action of molnupiravir that is primarily based on RNA mutagenesis mediated via the template strand.

In Vivo:

The efficacy of the MK-4482 prodrug was next assessed in the Syrian hamster model, which is regarded as a preclinical model of mild disease, with animals having self-limiting pneumonia.. Given the possibility for oral dosing, the utility of MK-4482 as a treatment following high-risk exposure was inspected. Two groups of hamsters (n = 6 per group) were treated with MK-4482 (250 mg/kg) by oral gavage 12 h and 2 h before (pre-infection treatment group) or 12 h post-infection (post-infection treatment group). Lung tissue samples were collected at the peak of virus replication and disease, day 4 post-infection, for analysis. In contrast to levels of shedding, a 1-log decrease in viral RNA was detected in the lungs of pre-infection and post-infection groups, respectively, when compared to the vehicle control group (Fig. 2d). This corresponded to a 2-log decrease in infectious virus in the lungs of the MK-4482 treated groups when compared to the vehicle controls (Fig. 2e). MK-4482 was not detected in the tissue. Then compared to the vehicle, viral genomes from MK-4482 treated animals had a significant accumulation of nucleotide substitutions (Supplementary Table 2). Together, these results are consistent with the RNA mutagenesis function of MK-4482 in the reduction of infectious virus and disease in treated animals. If adequately priced for widespread global use, MK-4482 should be considered as an oral postexposure application for SARS-CoV-2.

References:

1. Sheahan TP, Sims AC, Zhou S, Graham RL, Pruijssers AJ, Agostini ML, Leist SR, Schäfer A, Dinnon KH 3rd, Stevens LJ, Chappell JD, Lu X, Hughes TM, George AS, Hill CS, Montgomery SA, Brown AJ, Bluemling GR, Natchus MG, Saindane M, Kolykhalov AA, Painter G, Harcourt J, Tamin A, Thornburg NJ, Swanstrom R, Denison MR, Baric RS. An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 in human airway epithelial cell cultures and multiple coronaviruses in mice. Sci Transl Med. 2020 Apr 6:eabb5883.
2. Hampton T. New Flu Antiviral Candidate May Thwart Drug Resistance. JAMA. 2020 Jan 7;323(1):17.
3. Toots M, Yoon JJ, Hart M, Natchus MG, Painter GR, Plemper RK. Quantitative efficacy paradigms of the influenza clinical drug candidate EIDD-2801 in the ferret model. Transl Res. 2020 Apr;218:16-28.

Products are for research use only. Not for human use.