Future-proof strategies in preventing SARS-CoV-2 virus entry

The SARS-CoV-2 virus that causes COVID-19 uses its surface spike (S) protein to invade cells. Following binding of the S protein to ACE2 receptors and activation by cell proteases, cell entry is accomplished by a complex sequence of S protein reconfigurations that result in fusion of the viral and host cell membranes and viral entry. As the major antigenic determinant and the target of neutralizing antibodies, the S protein is a critical target for efforts to develop antivirals and an effective vaccine. The mechanism of S protein-mediated cell entry remains poorly understood, and the S protein structure is only partially determined. In this project, students will design a unified experimental/computational research program aiming to reveal the entry mechanisms, and to use this knowledge to assess the likelihood of success of proposed antiviral or prophylactic strategies to intercept entry. Students will design a human tissue system suitable for large-scale experimental modeling with a SARS-Cov-2 pseudovirus, in which the primary structure of the viral S protein, the capsid, the receptors or the activating proteases presented by the tissue can be altered by gene editing. In parallel, students will use computational methods to investigate the S protein structure, and to design simulation methods that can reveal the S protein mechanisms, motivate new antiviral approaches and assess existent proposals. An emphasis will be given to devising strategies that will be immune to potential advantageous mutations, using a high-throughput mutate-simulate-test approach. For this summer, the experimental portion of the project will only be designed in theory, however students interested in testing their predictions will have the opportunity to pursue the experimental part in the Simunovic lab next academic year.