The Ebola virus uses a single protein, GP, as a key to unlock and enter human cells, and this project will watch that protein move in real time to find new ways to block it. Current treatments for Ebola are limited, partly because scientists do not fully understand how GP changes shape during infection or how the body’s best antibodies stop it. This project fills that gap by building a biophysical toolkit that tracks GP’s structural shifts as it responds to pH changes, enzyme digestion, and receptor binding on the surface of virus-like particles. The researcher will combine hydrogen-deuterium exchange mass spectrometry with dynamic mass photometry to map exactly how human antibodies latch onto GP, including how multiple antibodies work together to neutralise the virus. If successful, the work could lead to data-driven designs for new nanobodies—tiny antibody fragments—that target GP more effectively than current candidates. Because the approach is designed to work on any enveloped virus, it could also speed up responses to future outbreaks of related pathogens, strengthening pandemic preparedness. This is fundamental science with a clear translational route: understanding a molecular lock to build better keys against it.
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The Ebola virus (EBOV) fusion glycoprotein GP mediates cell entry and is the main virus antigenic target. The molecular mechanisms underlying entry and antibody-mediated neutralization remain largely unknown, but are crucial for developing efficient therapies. To uncover these mechanisms, I will develop cutting-edge biophysical approaches that capture GP structural dynamics and host interactions during the EBOV lifecycle on membrane surfaces reflecting the authentic virus, with the overall aim of designing alternative candidate antivirals. I will establish a hydrogen-deuterium exchange mass spectrometry (HDX-MS) platform capable of tracking the conformational trajectory and molecular switches of GP embedded in virus-like particles undergoing the step- wise transitional events leading to EBOV entry (pH changes, lysosomal proteolysis and receptor binding). I will combine dynamic mass photometry with HDX-MS to derive a full picture of how human monoclonal antibodies engage GP, at the conformational and macro-molecular level, deciphering antibody multivalency, binding mechanisms and the immune response synergy that underlie EBOV neutralization. I will exploit these insights to develop data-driven computational approaches to rationally design GP-targeting neutralizing nanobodies of potential therapeutic success. This integrated approach will be both unique and broadly applicable to study the infectious processes of emerging and established enveloped viruses, thus contributing to pandemic preparedness.
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