Gellman lab works on ways to block SARS-CoV-2 from entering cells

By Tatum Lyles Flick
Department Communications

Man standing in front of experiment
Postdoctoral researcher Victor Outlaw synthesizes amino acids for
incorporation into peptides.

Prof. Samuel Gellman and his group have been working on strategies to prevent infection by pathogenic viruses for several years. They are now using that work as a launching pad for research on SARS-CoV-2, the virus that causes COVID-19.

This work, led by postdoctoral scientist Victor Outlaw, includes collaborations with virologists from Columbia University Medical Center (Anne Matteo and Matteo Porotto) and a group in Galveston, TX. The Columbia-Wisconsin team has previously designed peptides intended to block the fusion of HPIV3 and RSV, enveloped viruses that target the respiratory system and are particularly dangerous to young children and the elderly.

SARS-CoV-2 is also an enveloped virus, which means that its viral particles are surrounded by a membrane that must fuse with a human cell membrane to cause infection. In the 1980s, scientists learned that blocking envelope-membrane fusion could prevent infection by HIV. A decade ago, the Gellman lab began developing a new approach to fusion inhibitors by working on anti-HIV compounds.

Their experience with other viruses enabled the Gellman lab and their collaborators to pivot to SARS-CoV-2 as the pandemic was looming. Since March, this trans-national team has been developing long, synthetic peptides and asking if those peptides can stop the virus from infecting human cells.

“Because we had the right collaborators and because we had a strategy that can map onto this problem, we had to try this,” Gellman said. “However, we understand that it is very difficult to develop new therapeutic agents, even for very large companies.”

Due to their previous work on RSV and HPIV3, the Gellman lab and their collaborators were able to make significant progress over the past six months. The first paper from this collaboration recently appeared in the journal mBio. The research efforts continue.

The long-term goal is to develop molecules that can be inhaled to block fusion and protect frontline care providers and susceptible populations from infection. Later they plan to see if the same compounds could be used to treat those who are already infected.

“We learned a lot from my initial project that we could apply directly to Coronavirus,” Outlaw said. “It allowed us to identify a fusion inhibitory peptide much faster. We synthesize a peptide derived from a specific domain on the spike protein of SARS-CoV-2, which binds once the fusion protein activates, preventing entry into the cell.”

Long peptides are rapidly degraded in biological environments, so the Gellman lab modifies the peptide backbone to slow that degradation. Creating such peptides requires a lot of work; however, the Gellman lab has a head start because of their experience creating inhibitors for other viruses.

“Working on something that has a potential direct application in the clinic has been one of the hallmarks of my time here,” Outlaw said. “It definitely makes you feel like you might actually make a difference in somebody’s health – in human health.”