New COVID19 inhibitors now in stock

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SARS-CoV-2 Viral Mechanisms – How does the virus cause COVID-19?

The global pandemic caused by the SARS CoV-2 virus in 2020 has created a critical demand for novel antiviral treatments, diagnostic methods and vaccines against the virus. Research into how it attacks the immune system and causes the disease COVID-19 that has caused the world-wide pandemic has been underway since 2019. We now know that the virus enters human host cells through the Angiotensin Converting Enzyme 2 (ACE2) receptors on cells commonly found in the lower respiratory tract, where it can then cause the persistent cough and fever associated with the disease1.

SARS CoV-2 is part of the Coronaviridae family of enveloped, positive-strand RNA viruses. These zoonotic viruses mostly infect amphibians, birds and mammals. However there are eight which infect humans, causing COVID-19, SARS and MERS1. Genetic analysis has found that the bat beta-coronavirus is most closely related to the human SARS CoV-2 virus. It is likely that cross-over to humans came from bats in the Hubei Province of Wuhan in China towards the end of 20192,3.

A Closer look at the SARS Genome:

The SARS-CoV-2 genome is among the largest known in viruses, at 30kb with at least 6 open reading frames. This virus has 4 main structural proteins, including its characteristic spike (S) glycoprotein, membrane (M), envelope (E) and nucleocapsid (N). It also encodes 2 protease enzymes, Mpro and PLpro, which may be crucial to the development of future treatments of COVID-192.

The main open reading frame or this virus, ORF 1ab, encodes the polypeptides pp1a and pp1ab which are cleaved by the main protease enzyme, Mpro. Cleavage of this polypeptide leads to the release of 16 non-structural proteins, nsp 1-16. The papain-like proteases, PLpro, cleave the two polypeptides at the boundaries of nsp1/2, nsp2/3, and nsp3/41. Many of these non-structural proteins are essential for viral replication, as they assemble into the replicase-transcriptase complex for RNA synthesis. Without them the virus would be unable to survive within its host. Mpro is a particularly good candidate for antiviral drug target for SARS-CoV-2 because of its high specificity to cleave after a glutamine residue. No human host cell proteases are known to have this activity, and so any inhibitors of this protease would be specific to the viral proteases2.

New to Apollo Scientific: COVID-19 Protease Inhibitors

This month, Apollo Scientific are introducing a range of 6 new protease inhibitors to our existing catalogue of 20,000 products. Recent research into the effects of different protease inhibitors has found that these existing compounds in particular have a strong inhibitory effect against Mpro and PLpro, and show great potential for therapeutics for COVID-19 in the near future (based on experimental evidence of low IC50 values):

 

BISN0322  Disulfiram CAS: 97-77-8

Inhibitor of the aldehyde dehydrogenase (ALDH1) enzyme for treating chronic alcoholism. Recently found to be a competitive inhibitor of the SARS-CoV-2 PLpro protease with an IC50 of 9.35μM2.

BISN0323  Shikonin   CAS: 517-89-5

Natural derivative from the roots of the species Lithospermum Erythrorhizon. Acts as a non-covalent inhibitor of Mpro with an IC50 of 15.75 μM6.

BISN0324   PX-12   CAS: 141400-58-0

1-methylpropyl 2-imidazolyl disulfide is an inhibitor of thioredoxin-1. Selenium-containing inhibitor that deactivates Mpro with an IC50 of 21.39 μM2.

BISN0325  TDZD-8   CAS: 32703-89-5

Likely an aggregate-based inhibitor of Mpro alongside other proteases. IC50 of 2.15μM2.

BISN0326  Boceprevir   CAS: 394730-60-0

Existing treatment for the Hepatitis C virus. Binds to the Cys145 residue of Mpro with an IC50 of 4.13μM7.

BISN0327  GC-376   CAS: 1416992-39-6

Known feline infectious peritonitis pro-drug that has shown to be a potent inhibitor of the Mpro protease by modifying the Cys145. IC50 of 400nM.7

 

1https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369385/

2https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331567/

3https://www.nature.com/articles/s41564-020-0771-4

4https://www.sciencedirect.com/science/article/pii/S0891584920311291

5https://www.nature.com/articles/s41586-020-2223-y?

6https://www.biorxiv.org/content/10.1101/2020.06.16.155812v1.full.pdf

7https://www.nature.com/articles/s41467-020-18096-2