Researchers at MIT have discovered the molecular structure of a protein found in the novel coronavirus, the school said earlier this month.
In a statement posted Nov. 12 to the MIT website, the school said the protein, called the envelope protein E, plays a “key role” in the virus’s ability to replicate itself and “stimulate the host cell’s inflammation response.”
If researchers can find a way to “block this channel,” the statement continued, then they might be able to reduce the “pathogenicity of the virus” and also obstruct viral replication.
“Our findings could be useful for medicinal chemists to design alternative small molecules that target this channel with high affinity,” said Mei Hong, an MIT chemistry professor and senior author of the research team’s new study, in the statement.
The paper from Hong’s team was published Nov. 11 in the journal Nature Structural and Molecular Biology. Its lead author was MIT graduate student Venkata Mandala, the statement said, and additional authors were MIT postdoc Matthew McKay, along with graduate students Alexander Shcherbakov and Aurelio Dregni, as well as Antonios Kolocouris, a pharmaceutical chemistry professor at the University of Athens.
At the outset of the pandemic, the statement said, Hong and her students decided to focus their efforts on one of the COVID-19 proteins. They settled on protein E, the statement said, partly because it’s similar to an influenza protein called the M2 proton channel, which Hong’s studied previously.
“We determined the influenza B M2 structure after about 1.5 years of hard work, which taught us how to clone, express, and purify a virus membrane protein from scratch, and what NMR [nuclear magnetic resonance] experimental strategies to take to solve the structure of a homo-oligomeric helical bundle,” Hong said in the statement. “That experience turned out to be the perfect training ground for studying SARS-CoV-2 E.”
The researchers cloned and purified the E protein in two and a half months, according to the statement. To determine the protein’s structure, the statement said, researchers embedded it into a lipid bilayer, similar to a cell membrane, and analyzed it with NMR.
The statement noted that the COVID-19 E protein looks nothing like the ion-channel proteins of the influenza and HIV-1 viruses. The difference, the statement said, is among the topics that Hong and her team will study in the future.
“This paper represents a clear step forward, reporting the first high-resolution structure of a channel domain formed by any member of the coronavirus envelope protein family, and opens the way to rationally design compounds to block envelope protein channel activity,” said Jaume Torres, an associate professor of biological sciences at Nanyang Technological University in Singapore, in the statement.
Torres wasn’t involved in the research, according to MIT.
The MIT statement said the researchers also found that two drugs, amantadine and hexamethylene amiloride, can block the entrance of the E channel, but they bind only “weakly” to the protein.
Stronger inhibitors, the statement said, could emerge as potential drug candidates for treating COVID-19.
“Even when the pandemic is over, it is important that our society recognizes and remembers that fundamental scientific research into virus proteins or bacterial proteins must continue vigorously, so we can preempt pandemics,” Hong said in the statement. “The human cost and economic cost of not doing so are just too high.”