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Proteomic Study of SARS-CoV-2, SARS-CoV Infections Points to Potential Drug Targets

NEW YORK — Researchers have put together a detailed picture of what occurs at the proteomic level when either SARS-CoV or SARS-CoV-2 enters a cell, which could help identify compounds with antiviral activity.

In the ongoing pandemic, SARS-CoV-2 has led to more than 136 million cases of COVID-19 and nearly 3 million deaths worldwide, according to the Johns Hopkins University Coronavirus Resource Center. SARS-CoV, meanwhile, caused an earlier outbreak in 2003 that led to about 8,000 people becoming ill and 774 deaths, according to the US Centers for Disease Control and Prevention.

Researchers from the Technical University of Munich and the Max Planck Institute of Biochemistry sought to better understand how viral proteins from SARS-CoV-2 and SARS-CoV interact with host cellular proteins. As they reported in Nature on Monday, they used mass spectrometry-based techniques to analyze more than 1,200 samples to investigate the effects of viral and host protein interactions and whether that interactome could be mined to help uncover drugs to treat COVID-19.

"There has been no comparable mapping for SARS-CoV-2 so far," co-author Matthias Mann from the Max Planck Institute of Biochemistry said in a statement. "In a sense, we have taken a close look at five dimensions of the virus during an infection: its own active proteins and its effects on the host proteome, ubiquitinome, phosphoproteome, and transcriptome."

The researchers introduced tagged viral proteins from either SARS-CoV-2 or SARS-CoV into a human lung carcinoma cell line. Using affinity purification followed by mass spectrometry, they analyzed 1,801 interactions between 1,086 cellular proteins and 24 SARS-CoV-2 and 27 SARS-CoV bait proteins.

From their resulting virus-host interactome, the researchers found that the viruses affect a range of cellular activities. They noted, for instance, that SARS-CoV-2 targets innate immunity regulators and DNA damage response mediators, and interacts with proteins involved in intracellular trafficking and cellular metabolism.

The researchers also examined the effects of these viral-host protein interactions on protein expression and on ubiquitylation and phosphorylation. As expected, both SARS-CoV-2 and SARS-CoV downregulated type I interferon response and activated a pro-inflammatory signature at the transcriptome and proteome levels. SARS-CoV, though, led to a higher activation of the NF-kB pathway, which the researchers said could reflect its decreased pulmonary disease severity, while SARS-CoV-2 led to higher expression of FN1 and SERPINE1, which may reflect an effect on TGF-β signaling.

Meanwhile, the researchers identified more than 1,000 ubiquitination sites differentially regulated by SARS-CoV-2 and SARS-CoV, including autophagy-related factors, as well as more than 4,600 phosphorylation sites that changed following infection with either virus.

These interactions, the researchers noted, point to potential viral vulnerabilities that could be targeted by drugs. They tested a panel of 48 drugs that modulate pathways perturbed by the viruses to find that the FLT3/AXL inhibitor gilteritinib, the AKT inhibitor ipatasertib, and the matrix metalloprotease inhibitors prinomastat and marimastat inhibited SARS-CoV-2 replication with little effect on cell growth.

This, they wrote, is a line of inquiry they are pursing further. "Currently, we are working on new anti-COVID-19 drug candidates that we have been able to identify through our analyses," senior author Andreas Pichlmair from TU Munich said in a statement. "I am convinced that detailed datasets and advanced analysis methods will enable us to develop effective drugs in a more targeted manner in the future and limit side effects in advance."