1327: A case for ivermectin

There are some potential drugs that target the 3-chymotrypsin like protease (3CLpro). This is the main protease which is essential for the replication of SARS-CoV-2. Investigators used computational molecular modeling to screen 3987 FDA-approved drugs, and selected 47 drugs and assessed their inhibitory effects on SARS-CoV-2 specific 3CLpro enzyme in vitro. Boceprevir, ombitasvir, paritaprevir, tipranavir, ivermectin, and micafungin were found to inhibit 3CLpro enzymatic activity. According to the 100 ns molecular dynamics simulation studies, ivermectin may need homodimeric form of 3CLpro enzyme for its inhibitory action. These molecules could help in the development of highly specific therapeutically viable drugs for the inhibition of SARS-CoV-2 replication either alone or in combination with drugs specific for other SARS-CoV-2 viral targets.

1. SARS-CoV-2 has 5′-untranslated region followed by 16 non-structural proteins (ORF1a and ORF1b complex), which is also termed as replicase complex, and the structural proteins such as spike (S), envelop (E), membrane (M), and nucleocaspid (N) protein, besides accessory proteins present towards the 3′ end.
2. The S protein of the virus binds to its receptor on the host cells - ACE2. This is followed by the fusion of the viral envelop with host cell membrane, and the viral genome is released into the cytoplasm. The viral genome (+ssRNA) hijacks the host ribosomes and translates to ̴ 800KDa large polypeptide (PP) chain. This newly formed PP chain is auto-proteolytically cleaved by two proteases such aspapain like proteases (PLpro) and 3-chyomotrypsin like protease (3CLpro), which are encoded by the viral genome, to give rise to multiple non-structural proteins (NSPs) need for the virus to replicate. 3CLpro is also known as the main protease (Mpro). It has a critical role to play in viral replication. PLpro and 3CLpro cleaves the PP chain into 16 NSPs. Of these 16 NSPs, 11 are generated by the 3CLpro, which makes this protease one of the major targets for developing anti-SARS-CoV drug.
3. The structural and other accessary proteins are generated through a mechanism known as sub-genome (Sg) translation. Sg’s are generated by discontinuous transcription from 5′ end of the anti-sense viral RNA.
4. Successful genome replication and translation is followed by assembly of NSPs, structural proteins and accessory proteins, along with positive-sense viral RNA genome, to develop a novel virion.
5. 3CLpro is crucial for viral replication and therefore, serves as an excellent drug target.
6. Boceprevir, ombitasvir, paritaprevir, tipranavir, and micafungin have been found to have partial inhibitory effect, while ivermectin blocked over 85% of 3CLpro activity of SARS-CoV-2.
7. The anti-viral activity of ivermectin mediated through the blocking of α/β1 importin is well-known. Scientists have now reported the inhibitory effects of ivermectin on 3CLpro enzyme of SARS-CoV-2. This represents a supplementary anti-viral mechanism of this drug towards SARS-CoV-2.

[Source: Communications Biology volume 4, Article number: 93 (2021)]

Dr KK Aggarwal

President CMAAO, HCFI and Past National President IMA