The molecule of natural origin that inhibits SARS-CoV-2

An international study involving the Institute of Nanotechnology of the Cnr (Consiglio Nazionale delle Ricerche) has found that quercetin acts as a specific inhibitor for the virus responsible for Covid-19, showing a destabilizing effect on 3CLpro, one of the key proteins for virus replication. The study is published in the International journal of biological macromolecules

The attention of the whole world is currently directed towards the search for a pharmacological remedy to fight the coronavirus SARS-CoV-2, responsible for Covid-19. The development of a vaccine is certainly the most radical solution to solve this problem and the first results in this direction are encouraging, but there are also other weapons available to fight a viral pandemic. The most famous case is given by the HIV virus responsible for AIDS, a disease for which mortality is currently set to zero for those who have access to medical treatment: a success achieved despite never having a vaccine, thanks to the development of powerful antiviral drugs that block the HIV-specific protease, a protein essential for viral replication. Some of these drugs have been tested on the SARS-CoV-2 virus, but have not shown the desired effect. The development of specific antiviral drugs for the coronavirus is therefore another major line of research to solve the Covid-19 pandemic.

In this context fits the new discovery that demonstrates that quercetin, a molecule of natural origin, functions as a specific inhibitor for SARS-CoV-2. This molecule has a destabilizing effect on 3CLpro, one of the main proteins of the virus, essential for its development and whose block of enzymatic activity is lethal for SARS-CoV-2. The result is the outcome of the research work conducted by Bruno Rizzuti of the Institute of nanotechnology of the National research council (Cnr-Nanotec) of Cosenza together with a group of researchers from Zaragoza and Madrid and it has been published in the International journal of biological macromolecules.

“Computer simulations have shown that quercetin binds exactly into the active site of the 3CLpro protein, preventing it from performing its function properly”, says Rizzuti, author of the computational part of the study. “This molecule is already at the moment on par with the best antivirals available against the coronavirus, none of which, however, is approved as a drug. Quercetin has a number of original and interesting properties from a pharmacological point of view: it is present in abundance in common vegetables such as capers, red onion and radicchio and it is known for its anti-oxidant, anti-inflammatory, anti-allergic and anti-proliferative features. Its pharmacokinetic properties are also known and it is well tolerated by humans”.

Furthermore, quercetin can be easily modified to develop an even more powerful synthetic molecule, thanks to its small size and particular functional groups present in its chemical structure. Since it cannot be patented, anyone can use it as a starting point for new researches.

“The study starts from an experimental characterization of 3CLpro, the main protease of SARS-CoV-2”, explains Olga Abian, of the University of Zaragoza and first author of the publication: “This protein has a dimeric structure, formed by two identical sub-units, each with an active site essential for its biological activity. In a first phase of the work, the sensitivity to various conditions of temperature and pH was studied with various experimental techniques: an important result because many groups are working on 3CLpro as a possible pharmacological target, due to the fact that it is strongly conserved in all the types of coronaviruses. For this protein, molecules have already been reported in the literature that act as inhibitors, but they cannot be used as drugs due to their side effects”.

“The most interesting part of this work is the experimental screening performed on 150 compounds, through which quercetin has been identified as a molecule active on 3CLpro”, concludes Adrian Velazquez-Campoy of the University of Zaragoza, who directed the research group and had previously worked on finding protein inhibitory drugs for the original SARS virus that caused the 2003 outbreak. “Quercetin reduces the enzymatic activity of 3CLpro due to its destabilizing effect on the protein. Obviously we expect a vaccine to be found, but drugs will still be necessary for people already infected and for those who cannot be vaccinated. The search for new molecules therefore aims to administer a combination of different compounds, to minimize drug resistance and the development of new viral strains”. The study was supported by the Fundación hna.

Who: Cnr-Nanotec, University of Zaragoza

What: Structural stability of SARS-CoV-2 3CLpro and identification of quercetin as an inhibitor by experimental screening, Olga Abian, David Ortega-Alarcon, Ana Jimenez-Alesanco, Laura Ceballos-Laita, Sonia Vega, Hugh T. Reyburn, Bruno Rizzuti, Adrian Velazquez-Campoy; International Journal of Biological Macromolecules, 164: 1693-1703, 2020;

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