Half of the world’s population is at risk of contracting malaria, which is caused by Plasmodium parasites. Despite extensive public health and biomedical measures, the incidence of malaria continues to rise, with over 200 million cases each year. A highly effective vaccine will likely be required to eradicate malaria; however, current vaccine candidates against Plasmodium falciparum have fallen short in great part because of a lack of understanding of immunity to the parasite at the molecular level. Our recent X-ray crystallography and cryoEM work has revealed structural details of antibody immunity against the malaria parasite. These molecular blueprints of parasite inhibition by antibodies are being leveraged as guides for the design of next-generation subunit vaccines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) macrodomain within the nonstructural protein 3 counteracts host-mediated antiviral adenosine diphosphate-ribosylation signaling. This enzyme is a promising antiviral target because catalytic mutations render viruses nonpathogenic. We conducted a massive crystallographic screening and computational docking effort, identifying new chemical matter primarily targeting the active site of the macrodomain. X-ray data collection to ultra-high resolution and at physiological temperature enabled assessment of the conformational heterogeneity around the active site. Neutron diffraction data is guiding hydrogen placement to improve docking calculations. Several hits have promising activity in solution and provide starting points for development of potent SARS-CoV-2 macrodomain inhibitors. The role of entropy in modulating binding affinity will also be discussed.