Coronavirus is a membrane-enveloped package decorated with “spikes†that protrude from its surface. These spikes interact with the host cell to initiate infection of that cell. The ability of coronavirus to spread to other cells depends on how well the spike interacts with its target host membrane. The part of the spike that controls this interaction is called the “fusion peptide†and its job is to insert into the host membrane to initiate the delivery its genetic cargo into the cell. However, the specifics of how the fusion peptide interacts with the membrane is still not known. In this project, various interactions between the fusion peptide with membrane surfaces that mimic different kinds of host cells will be studied. This information will provide insight into the characteristics of both the fusion peptide and the host cell that promotes their interaction, and ultimately, infection and viral transmission to new hosts. With a better understanding of the science behind this critical interaction for virus adaptation to new hosts, we will be better informed about how this virus spreads and ultimately equipped to develop strategies to stop it. This fundamental information has the potential to enable fresh approaches to the design of antiviral drugs that target the fusion peptide. Given that the fusion peptide is highly conserved across the coronavirus family, these studies will be directly applicable to all coronaviruses, including the coronavirus that causes COVID-19.
A key determinant of the ability of coronavirus to spread is how it interacts with its target host membrane. For coronavirus, entry into a host cell is mediated by a single glycoprotein protruding from its membrane envelope, called spike (S). Within S, the region that directly interacts with the membrane is called the fusion peptide, FP. It is the physico-chemical interactions of the FP with the host membrane that anchors it, thus enabling the necessary deformations of the membrane that lead to delivery of the viral genome into the cell. Thus, understanding FP interactions at the most fundamental level will facilitate the development of strategies to limit those interactions to stop the spread of infections. This information is expected to be helpful in predicting the characteristics of emerging strains that could post a threat to humans in the future. The objective of this project is to measure and identify the specific intermolecular interactions responsible for insertion of FP into membranes. Specifically, this project will: 1) elucidate the factors that control hydrophobic interactions of FP using single molecule force measurements with atomic force microscopy and models of biological membranes, and 2) characterize the structure-function relationship of the FP using circular dichroism and isothermal calorimetry to correlate specific interactions with amino acid sequence and host surface properties. The intellectual merit of this project is discovering how changes in host membrane chemistry or amino acid sequence of the FP modulates the hydrophobic interaction and ultimately influences activity critical to the spread of infection. The broader impact of this project is providing information that will enable fresh approaches to the design of antiviral drugs, as well as to identify basic design rules that inform how the FP promotes the interaction with membranes of specific chemistry to predict host susceptibility to infection. Given that the FP is highly conserved across the CoV family, these studies will be directly applicable to all CoVs, including those yet to emerge.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
