Human proteins behind COVID-19 infection revealed by innovative CRISPR technology

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In the search for new treatments for COVID-19, a team led by researchers at the University of California, San Francisco, has identified a potential new drug target that may prevent infection with SARS-CoV-2. The protein, called BRD2, regulates the ACE2 receptor, which the novel coronavirus depends on to enter its host’s cells.

In their new study, published Jan. 13 in Nature Cell BiologyIn the study, the researchers found that blocking BRD2 production prevents the virus from infecting a variety of human cell types.

“We learned that BRD2 regulates the expression of other genes, including those that help promote tumor growth in some cancers,” said Martin Kampmann, PhD, associate professor of biochemistry and biophysics and senior author of the study. “Having discovered how the protein regulates ACE2, it means that the pathway could potentially be manipulated to make it more difficult for SARS-CoV-2 to infect cells.”

Unlike many of the proteins being studied as potential targets against COVID-19, BRD2 is not produced by the cells of its human host. The protein and other related components are currently being investigated in clinical trials as targets for cancer drugs.

Focus on the gatekeeper in ACE2

Researchers have discovered that BRD2 regulates ACE2 while searching for human host proteins that affect the ability of SARS-CoV-2 to bind to different types of cells grown in laboratory cultures, including cells of the lungs, heart, and nasal cavities — tissues that are particularly vulnerable to infection and long-term damage. due to COVID-19

Scientists examined 2,325 cellular proteins that they thought might influence COVID-19 infection by influencing the virus’s interaction with human cells. They determined that current drugs that target BRD2 could thwart COVID-19 infection in susceptible cell types, as well as in hamsters.

“We were surprised to see that knocking down BRD2 has roughly the same effect on inhibiting ACE2 production and infecting COVID-19 as directly affecting ACE2 itself,” Kampmann said.

The research team also included Avi Samilson, PhD, a postdoctoral fellow in the Kampmann lab, and Ruelin Tian, ​​PhD, a former graduate student in the lab who is now an assistant professor at Southern University of Science and Technology in Shenzhen, China. They, along with other members of Kampmann’s lab, which usually focus on neuroscience, proposed the study out of a desire to contribute to a better understanding of COVID-19. Working with members of UCSF’s Quantitative Biological Sciences Institute (QBI) coronavirus research group and collaborators recruited from around the world, the team identified several other cellular proteins that are potent enhancers and inhibitors of ACE2 production.

However, the researchers caution that this new study is only a first step, and more studies will be needed to establish the safety and efficacy of any drug directed at BRD2 or other newly identified targets.

For example, the team found that inhibiting BRD2 also suppresses production of interferon, a key protein in the body’s inflammatory response.

“It is important to learn more about these potential side effects,” Samelson said. “We don’t know if this effect on the immune system would be harmful or beneficial to an infected patient, and under what circumstances.”

CRISPR technology helps search for drug targets

Kampmann is best known for creating innovative new laboratory technologies based on powerful gene-editing technology, CRISPR, which is engineered through a unique biochemical mechanism that bacteria use to fight the viruses they infect.

Scientists first used CRISPR less than a decade ago to direct pieces of DNA at specific locations along the genome, and are now using the technology to edit DNA in a wide variety of organisms.

Kampmann and colleagues modified the original bacterial enzyme used in CRISPR so that instead of cutting DNA, it transports regulatory molecules to specific sites within the genome. Once there, these regulatory molecules can activate or repress genes, bypassing normal gene expression.

This ability to tune gene expression up or down is a useful way to identify drug targets, Kampmann said. “Suppression of genes and their products with CRISPR could mimic their inhibition by drugs and reveal targeted drugs that may be therapeutically useful.”

Another benefit is that these CRISPR assays are unbiased, meaning that researchers are not looking for a specific result, but rather systematically testing each protein to see which one has the desired effect, said Tian, ​​who aims to continue studying COVID-19 in China. .

“Using this robust approach helps us find many potential targets that we might not otherwise see,” he said. “By doing so, this screening helps facilitate new strategies to fend off infection with SARS-CoV-2 and its variants.”

An antibody has been found to inhibit a wide range of Sarpicviruses

more information:
Ruilin Tian, ​​BRD2 inhibition prevents SARS-CoV-2 infection by reducing ACE2 host cell receptor transcription, Nature Cell Biology (2022). DOI: 10.1038/s41556-021-00821-8.

Provided by University of California, San Francisco

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