They say you should keep your friends close and your enemies closer. By that logic, scientists say the more we know about viruses—down to their intricate molecular structures—the better we’ll be at defeating them.
Congbao Kang, a Group Leader of the Structural Biology team at A*STAR’s Experimental Drug Development Centre (EDDC), explained that until now, most drug discovery efforts to combat SARS-CoV-2 have focused on the N-terminal region of the virus’ spike protein, for its role in gaining entry into host cells.
However, because the spike protein is particularly prone to mutations, these treatments can eventually be rendered ineffective.
Kang’s team took a divergent approach, zeroing in on a specific part of the spike protein called the transmembrane domain (TM) instead. Thought to provide both flexibility and stability to the spike protein, TM domain's dynamics during COVID-19 infections have remained elusive.
“The structural analysis of TM proteins can be challenging due to the nature of the transmembrane regions,” said Kang. “To effectively study these proteins, it is necessary to use membrane-mimicking systems that replicate their native environment.”
In their study, Kang and colleagues collaborated with a researcher from the Guangdong Academy of Sciences, China, to analyse the TM structure at high resolution with the help of microscopic ‘bubbles’ called micelles. These contain both water-loving and water-repellent environments that mimic the lipid bilayers of human cell membranes and help stabilise the TM proteins.
After visualising the TM-containing micelles using nuclear magnetic resonance spectroscopy, Kang’s team observed that the viral protein formed a characteristic helical structure. They also identified a linker that acted like a flexible bridge between the TM helix and HR2 region in the spike protein.
In addition to these never-before-seen glimpses of the TM domain’s architecture, the team also identified particular regions of the protein that can bind to small molecules—a feature which can be crucial for developing antiviral therapies.
The team is currently deploying alternative membrane systems to examine the delicate complexity of TM structures. Kang’s team is also interrogating mechanisms in which small molecule inhibitors can bind to the TM domain to inhibit the infectivity of the SARS-CoV-2 spike protein.
The A*STAR-affiliated researchers contributing to this research are from the Experimental Drug Development Centre (EDDC).