Facing an unknown enemy is more dangerous than fighting with things we acquaintance with. So does our body when facing with a new pathogen. We have innate immunity as our first line defense to deal with the pathogens e.g. natural killer cells and dendritic cell. But what are drugs that act as antiviral for SARS-CoV-2 ?
Protease is an enzyme that break the proteins into smaller polypeptides or amino acids. In human, proteases are TMPRSS2, cathepsins, plasmin etc.
SARS-CoV-2 has main protease and scientists call it as Mpro, also known as 3C-like protease 3CLpro or Nsp5 which is recognized as a prime target for antiviral drug discovery. By using large-scale x-ray
crystallographic screen of Mpro, scientists in Germany obtained x-ray diffraction datasets for compounds in the virus.
The study found 43 compounds binding to Mpro, with nine compounds that reduced viral RNA (vRNA) replication i.g. showing antiviral activity against SARS-CoV-2.
- Calpeptin (attenuates apoptosis and intracellular inflammation changes in muscle cells) and Pelitinib (anticancer) showed strong antiviral activity with low cytotoxicity and are suitable for preclinical evaluation, followed by Triglycidyl isocyanurate (antitumor agent) and RS-102895 (for obstructing the immune suppressive effects of monocytes during early vaccine responses).
- Another drugs they found with moderate antiviral activity were AT7519 (anticancer), Quipazine maleate (bind to serotonin receptor), Ifenprodil (neuroprotective, anti-inflammatory)
- MUT056399, antibacterial agent against multidrug-resistant Staphylococcus aureus strains.
Another study from Australia, focusing on treatments using the knowledge previously gathered from SARS and MERS coronaviruses. They suggested that a two-armed clinical approach, focusing on the combinatorial inhibition of host/virus protease dependent viral entry and controlled immune response, could be applied for a more robust response against SARS-CoV-2.
Researchers from China used the accelerated FEP-ABFE predictions for drug repurposing targeting SARS-CoV-2 Mpro. They identified 16 potent inhibitors of SARS-CoV-2 Mpro from existing drugs. The identified most potent SARS-CoV-2 Mpro inhibitor is DIP, prodrug candesartan cilexetil, candesartan, hydroxychloroquine and chloroquine.
Indian researchers reported Ivermectin as a blocker of viral replicase, protease and human TMPRSS2, which could be the biophysical basis behind its antiviral efficiency. The antiviral action and ADMET profile of Ivermectin was on par with the currently used antiCOVID-19 drugs such as hydroxychloroquine and remdesivir.
Ivermectin homologs can bind with both S1 and S2 of the SARS-CoV-2 Spike protein. But, the strength of the binding of Ivermectin isomers were more intense on the S2. Thus, induced a conformational change in the whole protein or receptor-binding S1.
For interaction of Ivermectin with SARS-CoV-2 main protease, the researchers found a strong hydrophobic interaction between the two. The binding efficacy of Ivermectin to SARS-CoV-2 replicase/RDRP was to found to be relatively high. Ivermectin was found to be the best in binding with viral replicase compared to hydroxychloroquine (HCQ) and remdesivir. This study also reported that Ivermectin may also target human ACE2 and TMPRSS2 for exerting its inhibitory action over SARS-CoV-2.
By using SARS-CoV-2 main proteases inhibitors, it's considerable to choose the right drugs for COVID-19. The above studies can be concluded that Ivermectin, HCQ, and some anticancer drugs can not be ruled out from the list of drugs for COVID-19. It's time for the whole world to save it's own country without depending on a global organization whom may be has been prolonging this pandemic.
Sources:
https://pubmed.ncbi.nlm.nih.gov/33811162/
https://www.frontiersin.org/articles/10.3389/fmolb.2020.00215/full
https://www.pnas.org/content/117/44/27381
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996102/#__ffn_sectitle