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Author : Dr K Aggarwal, President CMAAO, HCFI, , With input from Dr Monica Vasudev
A case for ivermectin
India
healthysoch
New Delhi, January 25, 2021 :
Potential drugs that target the 3-chymotrypsin like protease (3CLpro), the main protease that is pivotal for the replication of SARS-CoV-2. Computational molecular modeling was used to screen 3987 FDA approved drugs, and 47 drugs were selected to study their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Our results indicate that boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin exhibited inhibitory effect towards 3CLpro enzymatic activity. The 100 ns molecular dynamics simulation studies showed that ivermectin may require homodimeric form of 3CLpro enzyme for its inhibitory activity. In summary, these molecules could be useful to develop highly specific therapeutically viable drugs to inhibit the SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.
- SARS-CoV-2 has 5′-untranslated region followed by 16 non-structural proteins (open reading frame; ORF1a and ORF1b complex) also called as replicase complex, and the structural proteins such as spike (S), envelop (E), membrane (M), and nucleocaspid (N) protein along with other accessory proteins present towards the 3′ end.
- The life cycle of the virus begins with the binding of the S protein of the virus to its receptor on the host cells, the ACE2. The binding is then followed by the fusion of the viral envelop with host cell membrane and the release of the viral genome into the cytoplasm7. The viral genome (+ssRNA) hijacks the host ribosomes and gets translated into ̴ 800KDa large polypeptide (PP) chain. The newly generated PP chain is auto-proteolytically cleaved by two proteases such as papain like proteases (PLpro) and 3-chyomotrypsin like protease (3CLpro), encoded by the viral genome, to generate several non-structural proteins (NSPs) required for the viral replication. 3CLpro is also called the main protease (Mpro) and plays a major role in the viral replication. PLpro and 3CLpro cleaves the PP chain into 16 NSPs and out of the 16 NSPs generated, 11 NSPs are generated by the 3CLpro, making this protease one of the major targets for developing anti-SARS-CoV drug
- On the other hand, structural and other accessary proteins are generated through a unique mechanism called sub-genome (Sg) translation. Sg’s are produced through discontinuous transcription from 5′ end of the anti-sense viral RNA.
- After successful genome replication and translation, NSPs, structural proteins and accessory proteins assemble along with positive-sense viral RNA genome to form a new virion.
- 3CLpro of SARS-CoV-2 as a target to identify potential inhibitors since this protease is indispensable for viral replication and hence an excellent drug target.
- Boceprevir, ombitasvir, paritaprevir, tipranavir, and micafungin exhibited partial inhibitory effect whereas, ivermectin blocked more than 85% of 3CLpro activity of SARS-CoV-2.
- Although the anti-viral activity of ivermectin mediated through the blocking of α/β1 importin is established, herein scientists report the inhibitory effects of ivermectin on 3CLpro enzyme of SARS-CoV-2, suggesting additional anti-viral mechanism of ivermectin towards SARS-CoV-2.
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