A team of researchers has made an important breakthrough in combating severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus that causes COVID-19. They have gained fresh insights into how the virus enters human cells and how it might be thwarted. Through a combination of simulations and theoretical models alongside structural data from their experimental partners, the team was able to construct a comprehensive view of the infection process at an atomic level.
The research team, spearheaded by Jose Onuchic from Rice University and Paul Whitford from Northeastern University, both associated with the National Science Foundation Physics Frontiers Center at the Center for Theoretical Biological Physics (CTBP) at Rice, has made a discovery in the battle against SARS-CoV-2, the virus that leads to COVID-19.
Working in conjunction with researchers Walter Mothes and Wenwei Li from Yale University, the team has revealed new understandings of how the virus infects human cells and how it can be inhibited. Their research findings were published in the journal Science on August 15.
The virus employs its spike protein to bind to the angiotensin-converting enzyme 2 on human cells, which kicks off a mechanism allowing it to infiltrate the cell. The spike protein comprises two key parts: the S1 domain, which exhibits considerable variation among different virus strains, and the S2 domain, which remains largely unchanged across various coronaviruses. This stability makes the S2 domain a promising candidate for vaccines and therapies that could be effective against a broad array of virus strains.
By integrating simulations and theoretical analyses with structural data from their experimental collaborators, which included the initial and final configurations as well as intermediate stages of viral invasion, the researchers achieved a granular view of the infection process down to the atomic level.
“Understanding these intermediate states of the spike protein paves the way for new treatment and prevention methods,” stated Onuchic, who holds the Harry C. and Olga K. Wiess Chair of Physics, and is a professor in physics and astronomy, chemistry, and biosciences, and co-director of CTBP. “Our work highlights the significance of merging theoretical and experimental strategies to address complex challenges such as viral infections.”
The experimental team at Yale utilized an advanced imaging technique known as cryo-electron tomography to take detailed snapshots of the spike protein during the fusion process.
They identified antibodies that specifically target a section of the S2 domain, referred to as the stem-helix, enabling them to attach to the spike protein and prevent it from reshaping into the form necessary for fusion. This action stops the virus from entering human cells.
“Our findings provide a clear understanding of how the spike protein alters its shape during infection and how antibodies can hinder this process,” Onuchic added. “This molecular knowledge opens up new avenues for creating vaccines and treatments aimed at a broad spectrum of coronavirus strains.”
The researchers combined theoretical modeling with experimental data to reach their conclusions. By merging simulations of the spike protein with experimental visuals, they were able to observe intermediate states of the protein that were previously unrecognized. This comprehensive approach facilitated their understanding of the infection process at an atomic scale.
“The collaboration between theoretical and experimental techniques was vital to our success,” claimed Whitford, a professor in the Department of Physics at Northeastern. “Our results reveal new potential therapeutic targets and development strategies for vaccines that could work against most virus variants.”
This team’s breakthrough is crucial in the ongoing struggle against COVID-19 and for preparing for future outbreaks of similar viruses. Targeting the conserved S2 domain could allow researchers to produce vaccines and treatments that remain effective as the virus evolves.
“This research represents a notable advancement in the fight against COVID-19 and other coronaviruses that may surface in the future,” stated Saul Gonzalez, director of the U.S. National Science Foundation’s Physics Division. “Gaining insight into the fundamental physical dynamics within complex biological systems is essential for crafting more effective and broad-spectrum treatments that can safeguard our health and save lives.”
This effort was supported by the National Science Foundation, National Institutes of Health, Canadian Institutes of Health Research, Canadian Research Chairs, and the Welch Foundation.
Additional researchers involved include Michael Grunst and Zhuan Qin from the Department of Microbial Pathogenesis, and Shenping Wu from the Department of Pharmacology at Yale; Esteban Dodero-Rojas at CTPB; Shilei Ding, Jérémie Prévost, and Andrés Finzi at the Centre de Recherche du CHUM; and Yaozong Chen and Marzena Pazgier at the Infectious Disease Division, F. Edward Hebert School of Medicine at the Uniformed Services University of the Health Sciences, as well as Yanping Hu and Xuping Xie from the Department of Biochemistry and Molecular Biology at the University of Texas Medical Branch at Galveston.
