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COVID-19

Mayaro Virus Antiviral EIDD-1931

Mayaro virus is a mosquito-borne virus endemic to forests in South America. It causes acute illness with fever, headache, rash, and long-lasting joint pain. Mayaro’s range could spread in the future because of climate change. No vaccines or antiviral drugs are currently available although there are some candidates under development.

Therefore, a concerned team of scientists from the Rega Institute for Medical Researchin Belgium wanted to do exploratory research on antivirals that might treat this disease. They chose a panel of molecules that are known to treat other mosquito-borne viruses, some of which block early stages of the virus life cycle (arbidol, chloroquine, suramin, and ribavirin), and some that inhibit virus genome replication (favipiravir, 7DMA, 2’CMC, EIDD-1931, galidesivir and remdesivir).

They then applied these selected molecules to a model of cell culture that was infected with Mayaro virus. The researchers measured the 50% effective concentration, or the amount of molecule that inhibits 50% of the virus infectivity. They optimized the antiviral screening assay to be reproducible and reliable.

The assay described in this paper can be useful to test future antiviral drugs against this virus. Furthermore, the three molecules that performed well in cell culture are worth further study with in vivo models. Although the range of Mayaro virus is limited for now, we should study it and other neglected diseases to proactively prevent suffering in the future.

 

Langendries L, Abdelnabi R, Neyts J, Delang L. Repurposing drugs for Mayaro virus: identification of EIDD-1931, Favipiravir, and Suramin as Mayaro virus inhibitors. Microorganisms. 2021 Mar 31;9(4):734. PMID: 33807492

Molnupiravir Against COVID-19

Molnupiravir is an antiviral drug that has recently been approved by the FDA for the treatment of COVID-19. This drug is especially exciting because it is the first approved COVID-19 drug that can be taken as a pill, and also because it reduces the risk of hospitalization and death by 30%. Two recent research papers give us insight into the molecular biology of how molnupiravir works.

In order to reproduce, the virus SARS-CoV-2 needs to synthesize RNA. Usually, the enzyme it uses to do this, RNA-dependent RNA polymerase (RdRp), is an attractive target for makers of antiviral drugs. At present, many antiviral drugs block RdRp by mimicking RNA nucleotides. When such a drug gets incorporated into a new RNA strand, synthesis stops. Unfortunately, this drug strategy is not effective against SARS-CoV-2 because it has proofreading enzymes that allow synthesis to continue.

Two research teams in Germany and Canada recently showed that molnupiravir mimics cytidine and uridine, two RNA nucleotides. Molnupiravir incorporates into new RNA strands, like other antiviral drugs. But interestingly, RdRp continues to synthesize RNA. How, then, does molnupiravir prevent severe COVID-19?

Both teams addressed this question by combining RNA that contained molnupiravir with RdRp in vitro. They found that when RdRp uses this RNA to synthesize new RNA, molnupiravir causes mutations. After several generations, mutations build up to a lethal level and the virus can no longer reproduce.

Molnupiravir’s mechanism of action evades viral proofreading enzymes. Because of this, it may also find use in treating a broad variety of other viruses that also have these enzymes.

 

Kabinger F, Stiller C, Schmitzova J, et al. Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nature Structural & Molecular Biology. 2021 Sep;28(9):740-746. PMID: 34381216

Gordon CJ, Tchesnokov EP, Schinazi RF, et al. Molnupiravir promotes SARS-CoV-2 mutagenesis via the RNA template. Journal of Biological Chemistry. 2021 Jul;297(1):100770. PMID: 33989635

FDA News Release: FDA authorizes additional oral antiviral for treatment of COVID-19 in certain adults

Remdesivir Synergy Against COVID-19

Currently, remdesivir is the only antiviral drug approved to treat COVID-19. Its effects on the course of disease are moderate. Many viral diseases, such as HIV and hepatitis C, are treated with drug cocktails. Existing antiviral drugs might make remdesivir more effective in combination.

Two research teams recently screened for antiviral drugs that might increase the effectiveness of remdesivir.

Lo et al. screened a library of drugs for its ability to reduce SARS-CoV-2 viral load in kidney epithelial cells. They found that simeprevir reduces viral load in vitro. Simeprevir is a protease inhibitor that is often combined with sofosbuvir to treat hepatitis C. Simeprevir was even more effective in the in vitro experiment when combined with remdesivir.

Nguyenla et al. added remdesivir to cell cultures of kidney epithelial cells and human lung cells and infected these cells with SARS-CoV-2. They used this remdesivir-treated culture to screen a large library of FDA-approved drugs for compounds that reduce a proxy measure of viral load. The team chose the twenty most promising drugs to validate in human lung cell culture, which they tested for viral load.

The drugs velpatasvir and elbasvir reduced viral load. Both velpatasvir and elbasvir are used as parts of drug cocktails to treat hepatitis C. Velpatasvir is used with sofosbuvir and elbasvir is used with grazoprevir. The research team then tested the velpatasvir/sofosbuvir and elbasvir/grazoprevir cocktails with remdesivir in lung cell culture; the three-drug cocktails were even more effective that the pairs.

These results support the idea that COVID-19 could be better treated with cocktails of antiviral drugs.

 

Lo HS, Hui KPY, Lai HM, et al. Simeprevir potently suppresses SARS-CoV-2 replication and synergizes with remdesivir. ACS Central Science. 2021 May 26;7(5): 792-802. doi: 10.1021/acscentsci.0c01186. PMID: 34075346

Nguyenla X, Wehri E, Dis EV, et al. Discovery of SARS-CoV-2 antiviral synergy between remdesivir and approved drugs in human lung cells. BiorXiv. Preprint. 2020 Sept. http://doi.org/10.1101/2020.09.18.302398

Chemicals for Pharmaceutical Research for the Novel Coronavirus, COVID-19

The coronavirus known as COVID-19 first appeared in December, 2019 and spread around the world within a matter of days. As of this writing, it has infected nearly 400,000 people in 169 countries.

Scientists around the world have stopped their normal research to focus on creating a vaccine and treatment for this illness which has killed more than 17,000 people worldwide. Fortunately, more than 100,000 have recovered.

On March 22, 2020, an international team of scientists published a research paper preprint on biorXiv analyzing the interaction between the novel coronavirus and human proteins.* Their analysis predicts 332 protein-protein interactions and 69 existing pharmaceuticals that might perturb these interactions. The researchers propose that these drugs may be candidates for treating COVID-19 infections.

 LKT Laboratories has a number of these proposed chemicals for COVID-19 research in stock that can be shipped within 24 hours:

We also have various other antiviral compounds available:

See complete list of available antiviral compounds here

*A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing, David E. Gordon et al., bioRxiv 2020.03.22.002386; doi: https://doi.org/10.1101/2020.03.22.002386.

LKT Laboratories is a biochemical supply company focused on the synthesis, purification, and isolation of small molecules for research applications. All laboratory activities, including synthesis, natural product isolation, and full analytical characterization of our products are performed at our headquarters in St. Paul, MN.  Call or email us if you have questions about the chemicals above or have a need for other chemicals not listed.