September: SARS-CoV-2 inhibitor drugs | News and features

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The leading journal of the Royal Society of Chemistry, Chemical Science, reports a new advance in the development of drugs specifically designed to inhibit an important SARS-CoV-2 enzyme. The international team, led by scientists from Oxford and Bristol Universities, has developed new peptide molecules and shown that they block (inhibit) the main protease of the virus. [Mpro] – a known target of SARS-CoV-2 drugs.

As soon as SARS-CoV-2 enters a healthy human cell, the virus’s own genetic material commands the machinery of the infected cell, forcing it to make new copies of the virus. An important step in this viral life cycle is to break down a very long “polyprotein” into its constituent viral proteins. SARS-CoV-2 has two molecular machines called protease enzymes that act as “molecular scissors”. One of them, the main protease or Mpro for short, has the crucial role of breaking up the polyprotein and cutting it in 11 different places.

In the early days of the pandemic lockdown, Oxford University Professor Garrett Morris brought together a group of scientists to try to understand Mpro with the aim of helping develop drugs for COVID-19. This group met weekly from Zoom for many months, combined their computational and experimental expertise, and included scientists from several different countries. These included Professors Adrian Mulholland and Jim Spencer, Dr. Deborah Shoemark, PhD student Becca Walters, and other colleagues. Using a wide range of computational molecular modeling techniques, including interactive virtual reality molecular dynamics, quantum mechanics, peptide design, and protein-ligand interaction analysis, scientists were able to create a picture of the structure, dynamics, and interactions of Mpro at the atomic level.

Using these models, the team was able to find out how Mpro’s viral “molecular scissors” work. Then they designed new peptides, which are short pieces of protein, as inhibitors that bind tightly to Mpro and prevent it from functioning, thereby stopping the virus from dead. But did they work?

All 11 protein interfaces and four of these designed peptides were synthesized and tested in the Chemistry Research Laboratory at Oxford University. Experiments led by Professor Chris Schofield at Oxford showed that the novel peptides – designed by Dr.

Adrian Mulholland, Professor of Chemistry at the University of Bristol and a lead author on the study, said: “Despite the development of successful vaccines in record time, there is an urgent need for new antiviral drugs. To date, there are no drugs that have been specially developed against COVID -19. Computational molecular modeling can really help with this. As we have shown here, computer design can produce molecules that actually prevent the Mpro enzyme from working. “

Dr. Deborah Shoemark, Senior Research Associate (Biomolecular Modeling) at the School of Biochemistry, added, “It was great to work together, combining our ideas and methods to get a really detailed picture of how this viral enzyme – and molecules, works to develop that will actually stop it.

Professor Mulholland added, “This collaboration really showed how sharing models, data and expertise can help develop understanding and move forward much faster. Garrett (Morris) built a fantastic team and it was exciting to work together on how science should be done – especially in the face of pressing issues like the COVID-19 pandemic. “

The study was funded by several grants, including support from the EPSRC, BBSRC, and Wellcome Trust.

paper

“Discovery of SARS-CoV-2 Mpro peptide inhibitors by modeling substrate and ligand binding” by Chan et al. Preprint on bioRxiv and in Chemical science


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