Toward New Antiviral Drugs

Research pinpoints mechanism and possible new therapies against multiple SARS-CoV-2 variants, other coronaviruses

Research

2 min read

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Scientists have taken an important step forward in understanding the features within a human cell that allow for coronavirus infections.

Investigators at Harvard Medical School, Dana-Farber Cancer Institute, and the Yale School of Medicine have identified a critical mechanism in human and other animal cells that regulates the expression of the ACE2 receptor, the entry point used by SARS-CoV-2 and other coronaviruses to enter cells and cause infections in humans and other animals.

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The work, published March 9 in Nature Genetics, can inform new therapeutic approaches that could make often-attacked cells, such as lung and airway epithelial cells, impervious to infection by a range of SARS-CoV-2 variants, as well as other coronaviruses.

The findings, the researchers say, suggest that drugs that inhibit this mechanism and block the expression of this receptor could be used to effectively shut the door to viruses that use it as their gateway. Such drugs could provide broad protection against viral infections caused by the rapidly mutating SARS-CoV-2, which have rendered many current therapies powerless.

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What is more, the researchers add, these new drugs could protect against existing and emerging coronaviruses that use the same receptor to infect humans and other animals.

Specifically, the team found that specialized groups of proteins within the cell nucleus, called mammalian SWI/SNF (BAF) chromatin remodeling complexes, work with another key nuclear protein called HNF1A to control the levels of the ACE2 cell-surface receptor that is required for SARS-CoV-2 infection. Importantly, the team’s experiments showed that when mSWI/SNF complexes were disrupted in various cell types, cells could no longer make ACE2 receptor protein and thus became resistant to infection by any virus that uses ACE2 for entry.

“If validated in further studies, our results may lead to the development of mSWI/SNF complex inhibitors in the setting of SARS-CoV-2 as means to block or reduce coronavirus entry into cells and prevent infection. Importantly, these drugs can help combat the ever-changing SARS-CoV-2, including remdesivir-resistant variants. And, since they do not target the virus itself and instead attack the host cells, the probability of the virus developing resistance to these molecules is likely reduced,” said study co-first author Ajinkya Patil, a graduate student in the HMS virology program.

Patil was part of a team led by Cigall Kadoch, HMS associate professor of pediatrics at Dana-Farber and an investigator of the Howard Hughes Medical Institute. Kadoch co-led the study with colleague Craig Wilen, of the Yale Cancer Center.

Kadoch’s work on mSWI/SNF complexes over the years has led to experimental drugs currently in phase 1 safety and efficacy trials as anticancer agents. The team’s findings suggest potential utility for SMARCA4/2 ATPase inhibitors beyond oncology.

Authorship, funding, disclosures

Additional authors included Jin Wei, Clayton Collings, Mia Madel Alfajaro, Yu Liang, Wesley Cai, Madison Strine, Renata Filler, Peter DeWeirdt, Ruth Hanna, Bridget Menasche, Arya Ökten, Mario Peña-Hernández, Jon Klein, Andrew McNamara, Romel Rosales, Briana McGovern, M. Luis Rodriguez, Adolfo García-Sastre, Kris White, Yiren Qin, John Doench, Qin Yan, Akiko Iwasaki, Thomas Zwaka, and Jun Qi.

The work was supported by NIH grant K08AI128043, Burroughs Wellcome Fund, Smith Family Foundation, Ludwig Family Foundation, Huffington Foundation, Mathers Foundation, Emergent Ventures Fast Grant, The Mark Foundation for Cancer Research, and the NIH Director’s New Innovator Award 1DP2CA195762-01.

Please see the paper for relevant disclosures.

Adapted from a Dana-Farber news brief.