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We are studying the mechanism of viral membrane fusion and its inhibition by drugs and antibodies. We use the HIV envelope protein (gp120/gp41) as a model system. Some of our studies are aimed at creating an HIV vaccine that elicits antibodies against a transient, but vulnerable, intermediate in the membrane-fusion process, called the pre-hairpin intermediate. We are also interested in protein surfaces that are referred to as "non-druggable". These surfaces are defined empirically based on failure to identify small, drug-like molecules that bind to them with high affinity and specificity. Some of our efforts are aimed at characterizing select non-druggable targets. We are also developing methods to identify ligands for non-druggable protein surfaces.