Chemistry Seminar [FFCEP] - Designing Supramolecular Protein Assemblies in the Fight Against Disease
Designing Supramolecular Protein Assemblies in the Fight Against DiseaseDr. José VillegasFulbright Postdoctoral Fellow & Zuckerman Postdoctoral ScholarDepartment of Structural Biology, Weizmann Institute of Science, IsraelAbstract:Traditionally, drug discovery has relied on the identification of molecules that bind with high affinity and specificity to a particular target of interest. Given the tremendous difficulty of accurately designing molecules that satisfy both of these criteria, the bulk of drug discovery is achieved by large-scale screening methods. To make matters worse, many disease-related protein targets are considered undruggable, as their structure makes the identification of such binders highly unlikely. Recently, significant progress has been made in the design of protein-based assemblies. This marks an opportunity to use supramolecular protein assembly as a mechanism for neutralizing disease-related targets. Supramolecular assemblies can be divided into two types—closed and finite, and open and infinite. Finite protein assemblies are spherical in shape and may have hollow interiors. These hollow assemblies, also referred to as protein nano-cages, have been proposed for use as drug-delivery vehicles, or antigen display surfaces for the development of vaccines. However, there is an inherent limit to the size of the particles that can be built using current design methodologies. This size limitation stems from the use of strictly symmetrical arrangements of protein subunits about a central point. I will discuss the design of nano-cages where this strictly symmetrical arrangement is broken, paving the way for the design of protein nano-cages of unprecedented size. I will also discuss how protein-based nano-cages could be used to selectively trap biological targets.Infinite protein assemblies propagate outward in one, two, or three dimensions, resulting in a transition from an aqueous to solid state. Biologically, these types of assemblies have been associated with pathologies such as sickle-cell disease and Alzheimer's disease. Protein design has been extensively utilized in the creation of infinite assemblies, but these efforts have been focused on the engineering of biocompatible materials. I will discuss strategies for inducing the infinite assembly of disease-related targets.Speaker Bio:Dr. José Villegas earned a BS in biochemistry from the University of California Santa Barbara, an MA in chemistry from Brooklyn College, and PhD in Chemistry at the University of Pennsylvania under the supervision of Prof. Jeffery G. Saven. His doctoral dissertation was on the computational design of protein-ligand and protein-protein interactions. He is now a Fulbright Postdoctoral Fellow and a Zuckerman Postdoctoral Scholar in the Department of Structural Biology at the Weizmann Institute of Science, Israel, where he is working to quantify the influence of protein composition on the interactions between proteins. Dr. Villegas has developed novel scoring functions from the statistical analysis of known protein-protein interfaces, and is working on developing anti-viral and anti-cancer agents based on the induced supramolecular self-assembly of biological targets.
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