Nav: Home

Targeting SARS-CoV-2 enzyme with inhibitors

June 09, 2020

WASHINGTON, June 9, 2020 -- As the COVID-19 pandemic caused by the coronavirus SARS-CoV-2 continues to spread around the world, many researchers are studying epidemiological models to predict its propagation.

However, Ernesto Estrada, a mathematician and expert in complex systems of the ARAID Foundation at the University of Zaragoza, decided to focus on finding targets within SARS-CoV-2 for new drugs to attack. From previous work, he knew that the main protease of the virus, an enzyme in charge of proteolytic processing of polyproteins, is an excellent target.

In the journal Chaos, from AIP Publishing, Estrada said when he and colleagues discovered a dramatic increase in the sensitivity of the main protease of SARS-CoV-2 to small disturbances, it made them suspect there is a role for inhibitors to play in killing the virus.

Inhibitors are organic molecules, drugs, or new chemical compounds that attach to a protease's binding site to inhibit its work. A virus will die without a proteolytic enzyme working for it.

"I noticed that chemists had already found some potent inhibitors of the main protease of SARS-CoV-2, and that they'd resolved the structure of this protein via X-ray crystallography," he said. "It was shocking to see that this protease is very similar to that of the SARS coronavirus, which produced the epidemics of 2003, SARS-CoV-1."

When researchers superimposed both structures on top of each other, they matched almost perfectly.

"If you line up the amino acid sequences of both proteases, there are only 12 out of 306 residues that don't coincide," Estrada said. "Is there something hidden behind these apparent similarities between the two proteases? Can we learn something from them to improve the design of drugs against the virus?"

Estrada's group has extensive experience in the analysis of networks -- like social networks, the internet, or food chains between species within an environment -- and decided to treat a protein as network.

"They're called protein residue networks, where we represent every amino acid as a node, and the interaction between two amino acids is represented by a link between the two," he explained.

They found several structures of the main protease of SARS CoV-1 and SARS CoV-2 that were clean, which means that they contain no mutations, ligands, or solvents within their structures. They transformed their structure into protein residue networks.

Estrada said most traditional network measures revealed both structures were very similar to each other, something his team already knew. "But a couple of years ago, we developed a more sophisticated mathematical measure that allows us to detect how far away a perturbation within a network can be propagated. That work was of a very theoretical, mathematical nature, but we had speculated that it could be useful for the study of proteins."

So they put it to the test. It revealed that the protease of SARS-CoV-2 is 1,900% more sensitive to the long-range transmission of perturbations than the protease of SARS-CoV-1.

"This means that when a protein is perturbed, for instance by water within the intracellular environment, such perturbations are transmitted through a network of intraresidues that form the 3D structure of the protein," Estrada said. "If such perturbation is produced around a given amino acid within the protease of SARS-CoV-1, it's transmitted only through a close environment around that perturbed amino acid."

But if this perturbation occurs to one amino acid within the protease of SARS-CoV-2, it is transmitted to almost the whole network -- even to amino acids very far away.

"It's remarkable, because it means that with tiny structural differences the protease of SARS-CoV-2 is much more effective within intraresidue communications," Estrada said. "It should be much more effective in doing its job as a proteolytic enzyme of the virus. The devil did a nearly perfect job here, but he left the door open. This great sensibility of the SARS-CoV-2 protease to perturbations can be its Achilles' heel in relation to inhibitors."

The group's approach can be used for massive screening protocols to identify potent inhibitors of SARS-CoV-2 main protease and, consequently, for the development of new drugs to kill it.
-end-
The article, "Topological analysis of SARS CoV-2 main protease," is authored by Ernesto Estrada. It will appear in Chaos, June 9, 2020 (DOI: 10.1063/5.0013029). After that date, it can be accessed at https://aip.scitation.org/doi/10.1063/5.0013029.

ABOUT THE JOURNAL

Chaos is devoted to increasing the understanding of nonlinear phenomena in all areas of science and engineering and describing their manifestations in a manner comprehensible to researchers from a broad spectrum of disciplines. See https://aip.scitation.org/journal/cha.

American Institute of Physics

Related Science Articles:

75 science societies urge the education department to base Title IX sexual harassment regulations on evidence and science
The American Educational Research Association (AERA) and the American Association for the Advancement of Science (AAAS) today led 75 scientific societies in submitting comments on the US Department of Education's proposed changes to Title IX regulations.
Science/Science Careers' survey ranks top biotech, biopharma, and pharma employers
The Science and Science Careers' 2018 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Science in the palm of your hand: How citizen science transforms passive learners
Citizen science projects can engage even children who previously were not interested in science.
Applied science may yield more translational research publications than basic science
While translational research can happen at any stage of the research process, a recent investigation of behavioral and social science research awards granted by the NIH between 2008 and 2014 revealed that applied science yielded a higher volume of translational research publications than basic science, according to a study published May 9, 2018 in the open-access journal PLOS ONE by Xueying Han from the Science and Technology Policy Institute, USA, and colleagues.
Prominent academics, including Salk's Thomas Albright, call for more science in forensic science
Six scientists who recently served on the National Commission on Forensic Science are calling on the scientific community at large to advocate for increased research and financial support of forensic science as well as the introduction of empirical testing requirements to ensure the validity of outcomes.
World Science Forum 2017 Jordan issues Science for Peace Declaration
On behalf of the coordinating organizations responsible for delivering the World Science Forum Jordan, the concluding Science for Peace Declaration issued at the Dead Sea represents a global call for action to science and society to build a future that promises greater equality, security and opportunity for all, and in which science plays an increasingly prominent role as an enabler of fair and sustainable development.
PETA science group promotes animal-free science at society of toxicology conference
The PETA International Science Consortium Ltd. is presenting two posters on animal-free methods for testing inhalation toxicity at the 56th annual Society of Toxicology (SOT) meeting March 12 to 16, 2017, in Baltimore, Maryland.
Citizen Science in the Digital Age: Rhetoric, Science and Public Engagement
James Wynn's timely investigation highlights scientific studies grounded in publicly gathered data and probes the rhetoric these studies employ.
Science/Science Careers' survey ranks top biotech, pharma, and biopharma employers
The Science and Science Careers' 2016 annual Top Employers Survey polled employees in the biotechnology, biopharmaceutical, pharmaceutical, and related industries to determine the 20 best employers in these industries as well as their driving characteristics.
Three natural science professors win TJ Park Science Fellowship
Professor Jung-Min Kee (Department of Chemistry, UNIST), Professor Kyudong Choi (Department of Mathematical Sciences, UNIST), and Professor Kwanpyo Kim (Department of Physics, UNIST) are the recipients of the Cheong-Am (TJ Park) Science Fellowship of the year 2016.
More Science News and Science Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: The Power Of Spaces
How do spaces shape the human experience? In what ways do our rooms, homes, and buildings give us meaning and purpose? This hour, TED speakers explore the power of the spaces we make and inhabit. Guests include architect Michael Murphy, musician David Byrne, artist Es Devlin, and architect Siamak Hariri.
Now Playing: Science for the People

#576 Science Communication in Creative Places
When you think of science communication, you might think of TED talks or museum talks or video talks, or... people giving lectures. It's a lot of people talking. But there's more to sci comm than that. This week host Bethany Brookshire talks to three people who have looked at science communication in places you might not expect it. We'll speak with Mauna Dasari, a graduate student at Notre Dame, about making mammals into a March Madness match. We'll talk with Sarah Garner, director of the Pathologists Assistant Program at Tulane University School of Medicine, who takes pathology instruction out of...
Now Playing: Radiolab

What If?
There's plenty of speculation about what Donald Trump might do in the wake of the election. Would he dispute the results if he loses? Would he simply refuse to leave office, or even try to use the military to maintain control? Last summer, Rosa Brooks got together a team of experts and political operatives from both sides of the aisle to ask a slightly different question. Rather than arguing about whether he'd do those things, they dug into what exactly would happen if he did. Part war game part choose your own adventure, Rosa's Transition Integrity Project doesn't give us any predictions, and it isn't a referendum on Trump. Instead, it's a deeply illuminating stress test on our laws, our institutions, and on the commitment to democracy written into the constitution. This episode was reported by Bethel Habte, with help from Tracie Hunte, and produced by Bethel Habte. Jeremy Bloom provided original music. Support Radiolab by becoming a member today at Radiolab.org/donate.     You can read The Transition Integrity Project's report here.