Nusrat, a junior studying Biochemistry and Sociology at Binghamton University, complemented recruiting chimeras as antimicrobial agents.
Bifunctional molecules are an emerging therapeutic modality that provides fundamentally new therapeutic strategies by inducing synthetic proximity between an effector and target of interest (e.g., PROTAC-mediated degradation). Looking back on my time at the Broad, I'm reminded of the philosophy that 'BSRP would provide the ingredients, not the cake' to the rest of our academic journey. This summer has been about so much more than a finished product – it’s been about the supportive community and the enduring friendships that expanded my understanding of what is achievable. Just as its appearance does not merely define a cake, but by the quality of its ingredients, my growth as a researcher and an individual has been shaped by the rich mix of support, collaboration, and learning the program has provided. This summer has equipped me with indispensable guidance and resources while allowing me to compose my distinctive narrative. I am deeply grateful for this opportunity and excited to direct the skills and connections I have nurtured toward my upcoming endeavors. However, the development of new classes of bifunctional molecules is limited by the lack of non-inhibitory ligands against effectors and targets of interest to facilitate recruitment. We have developed a new class of bifunctional molecules that allows for direct recruitment of complement components to pathogens to empower the immune system to eliminate difficult-to-treat pathogens. The complement system is a vital component of the immune system that consists of a complex group of extracellular proteins that work together to defend against pathogens. Complement proteins are in high abundance in the blood that may be leveraged via bifunctional recruitment. Pseudomonas aeruginosa (PsA) is a challenging bacterium to treat due to its ability to cause various infections and antibiotic resistance. Herein, we employed our DNA-encoded library (DEL) screening platform and our custom in-house DEL analysis app to discover ligands against complement and PsA surface proteins for bifunctional development. After DEL screening and Structure-Activity Relationship (SAR) analysis, top hits were nominated for binding validation via Surface Plasmon Resonance (SPR) and Bio-Layer Interferometry (BLI). The hits were then conjugated through a linker via click chemistry to form bifunctional molecules that displayed complement-dependent cytotoxicity against bacteria. Collectively, these studies describe the discovery of the first non-inhibitory complement protein binders and their application in developing a new class of antimicrobial bifunctional modality.
Project: Complement Recruiting Bifunctional Molecules as a New Antimicrobial Modality Enabled by DNA-Encoded Library Screening
Mentors: Zachary Severance
PI: Choudhary Lab