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Structure-Based Vaccine and Drug Discovery

Despite the tremendous successes of current vaccines, many infectious diseases still persist among global populations and represents paramount threats against global public health, such as AIDS and malaria. These global padamics provide strong rationale for broadening our vaccine development repertoire. Structural vaccinology, in which protein structure information is utilized to design immunogens, has promise to provide new vaccines against traditionally difficult targets. High-resolution atomic structures of antigens containing one or more protection epitopes, especially in the form that are commonly seen by the immune system or in complex with a protective antibody, are the starting point for immunogen discovery. Integrating structure and sequence information for families of broadly neutralizing antibodies (bNAbs) has recently enabled the creation of germline-targeting immunogens that bind and activate germline B-cells in order to initiate the elicitation of such antibodies. The molecular contacts between antigen and neutralizing antibody define a structural epitope; methods have been developed to transplant epitopes to scaffold proteins for structural stabilization, and to design minimized antigens that retain one or more key epitopes while eliminating other potentially distracting or unnecessary features. To develop vaccines that protect against antigenically variable pathogens, pioneering structure-based work demonstrated that multiple strain-specific epitopes could be engineered onto a single or few immunogens.

Much like structure-based vaccine discovery, the field of structure-based drug design is a rapidly growing area in which many successes have occurred in recent years. The explosion of genomic, proteomic, and structural information has provided hundreds of new targets and opportunities for future drug lead discovery. The process of structure-based drug design includes, primarily, the choice of a target, the evaluation of a structure of that target, the pivotal questions to consider in choosing a method for drug lead discovery, such as virtual screening on supercomputer, and evaluation of the drug leads either computationally or experimentally. In the IPCCSB, we are developing advanced supercomputing tools, combined with the state-of-the-art techniques in cryo-electron microscopy to advance stucture-based vaccine and drug discovery.