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Author: Jean-Claude Muller, 穆卓Executive Editor at BtoBioInnovation  jcm9144@gmail.com

SPECIAL REPORT #20.19

Mpro: A potential antiviral target for a SARS-CoV-2

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is slowly decreasing in many countries around the world, in spite of the lack of efficient treatments. Unprecedented scientific efforts are still ongoing to discover useful and safe vaccines as well as potent antiviral agents.

Several reports have been published describing the race to develop a COVID-19 vaccine and data from the World Health Organization (WHO) showed that more than 100 potential vaccines against SARS-CoV-2 are currently under development with already half a dozen of them tested in the clinic.

Far less is currently known about similar efforts to discover and develop potent and selective antiviral agents. As of today, remdesivir, a repurposed drug, is the only drug approved for the treatment of COVID-19, although its clinical benefits are clearly limited and the medical community is looking for better treatments.

A thorough investigation of the structure and the replication mode of SARS-CoV-2 has identified a protein that is essential for the reproduction of the virus. The protein, called main protein (Mpro, also termed 3CLpro), is a proteolytic enzyme that processes polyproteins, that are translated from viral RNA to make functional viral proteins. Such proteases are highly attractive drug targets because of their major role in viral replications. Proteases (endopeptidases, metalloproteases, converting enzymes, cysteine proteases, …) are well known biological targets which have already been successfully tackled by chemists to produce highly effective and selective drugs for various treatments such as hypertension and HIV/AIDS.

A team from the University of Lübeck in Germany, led by Professor Rolf Hilgenfeld, using high intensity X-ray beaming, found that SARS-CoV-2 and SARS-CoV share 96% of their Mpro amino acid sequence with differences at just 12 out of 303 positions.

Ernesto Estrada, a mathematician, from the University of Zaragoza in Spain, has studied the topological characteristics of the networks of both enzymes and shown that SARS-CoV-2 Mpro is 1,900% more sensitive than SARS-CoV Mpro in transmitting tiny structural changes across the entire network.

These observations open a new avenue for massive screening protocols to identify and design selective and potent SARS-CoV-2 protease inhibitors. If the hypothesis is proven correct, we should rapidly hear about the emergence of a far better antiviral agent that the current remdesivir.

Paris, June 11, 2020.

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