Sunshine Biopharma Inc (SBFM)

[MJP2020]

According to a PR released on Feb 25, 2022: Quote: At the University of Arizona, the research effort will focus on determining the in vivo safety, pharmacokinetics, and dose selection properties of 3 university owned PLpro inhibitors followed by efficacy testing in MA10 mice infected with SARS-CoV-2.  Molecules showing efficacy in infected mice will be advanced to human trials.
 
"We are delighted to be working with the University of Arizona Coronavirus research team led by Dr. Gregory Thatcher as well as the commercialization team at Tech Launch Arizona”

Here is the research paper published on Feb 9, 2022 by Dr. Thatcher’s team from University of Arizona:

Dual Inhibition of Cathepsin L and 3CL-Pro by GC-376 Constrains SARS Cov2 Infection Including Omicron Variant

https://www.biorxiv.org/content/10.1101/2022.02.09.479835v1.full

Quote:
Clinical trial results showed far from optimal activity of remdesivir in inhibiting SARS CoV2 replication (9) and the reasoning for this suboptimal therapeutic efficacy of remdesivir could be that targeting RNA polymerase alone may not be sufficient to clear or control viral load in many severe/hospitalized cases of COVID19. Therefore, targeting additional key steps in SARS CoV2 infection such as virus entry could be critical. Recently, the FDA has granted Emergency Use Authorizations (EUAs) for two drugs namely, molnupiravir and nirmatrelvir/ritonavir for treating COVID19 patients which have shown better efficacy than Remdesivir (10). Two host enzymes, TMPRSS2, and cathepsin-L, are known to be critical for mediating virus entry. Two major virus proteases namely, 3-chymotrypsin-like proteases (3CL-Pro) and papain-like proteases (PL-Pro), are necessary for the processing of several non-structural proteins (NSPs) needed for viral replication, and these virus proteases are attractive targets for antiviral drugs (24, 25). Here, we investigated the key factors regulating SARS CoV2 entry such as cathepsin-L and TMPRSS2 using 293T cells overexpressing human ACE2 (26). Several reports that emerged during the initial phase of the COVID19 pandemic emphasized TMPRSS2 as the most important host factor mediating SARS CoV2 entry and indicated TMPRSS2 inhibition as a therapeutic option for COVID19 (13, 27, 28). Earlier, we had shown that the cathepsin-L cleavage site was conserved in envelope proteins of different families of viruses such as SARS-CoV and Ebola, Hendra, and Nipah viruses, and inhibition of cathepsin-L led to inhibition of entry of these viruses into host cells (18). Using CRISPR gene deletion and pharmacological inhibition, we showed that cathepsin-L could play a more robust role in mediating SARS CoV2 entry into human 293T ACE2 cells than TMPRSS2. These results were consistent with reduced SARS CoV2 induced CPE in CTSLKo 293T-ACE2 cells compared to TMPRSS2™ 293T-ACE2 cells.

We screened 5,370 compounds in the TargetMol Bioactives library, a collection of heavily annotated small molecules, including clinically-tested and FDA-approved compounds, and identified 27 compounds with significant cathepsin-L inhibitory activity and potential drug-like properties. Of those 27 compounds, 3 compounds namely, leupeptin hemisulfate, Z-FA-FMK, and GC-376 inhibited SARS CoV2 pseudovirus entry as well as SARS CoV2 induced CPE in 293T ACE2 cells with sub-micromolar IC50 values. More importantly, these drugs inhibited SARS CoV2 induced CPE under both pre-and post-treatment conditions suggesting that the mode of action involved not only a viral entry step but a subsequent step as well.