Massachusetts General Hospital
My career to date has been dedicated to becoming an independent physician-scientist. After completing PhD training in 2012 and MD training in 2014 at the University of Minnesota, I have gone on to training in Internal Medicine at Massachusetts General Hospital (MGH) from 2014-2017 and to subspecialty training in Infectious Diseases in the joint MGH / Brigham & Women’s Hospital fellowship program from 2017-2019. I am currently a practicing infectious diseases physician-scientist engaged in the development of therapeutics aimed at combating infectious diseases.
In 2018, I joined the lab of Brad Pentelute in the Massachusetts Institute of Technology (MIT) Department of Chemistry, where my work has focused on adapting Pentelute lab expertise in fast flow peptide synthesis and affinity selection mass spectrometry to the development of therapeutics based on peptidomimetic derivatives of human miniprotein effectors of innate immunity. Specifically, I have used systematic evaluations of structure-activity relationships in the human miniprotein effector LL-37 to define key parameters governing potency and toxicity, and I have incorporated these into the design of smaller peptidomimetic leads for the treatment of gram-negative bacteria. This work also led to the surprising finding that, despite the common belief that LL-37 kills bacteria through membrane permeabilization, selected derivatives of LL-37 demonstrate marked reductions in membrane permeabilization while retaining full antimicrobial activity. Characterization of LL-37-resistant Pseudomonas from patients with cystic fibrosis and other mechanistic studies are ongoing.
My ultimate goal is to be able to plug peptidomimetics into a system for synthetic directed evolution that can fine-tune properties such as cell type / tissue affinity and potency. Toward this end, I have developed a reworked approach to affinity selection-mass spectrometry that makes it feasible to engage in the directed evolution of synthetic therapeutics that straddle the line between small molecules and biologics. This reworked methodology also dramatically increases the theoretical synthetic capacity of this system, opening up several new angles to the exploration of chemical space. My broader vision is to deploy this technology as a platform for therapeutic development, starting with antimicrobials and immunomodulators for the treatment of gram-negative and mycobacterial infections as well as designer adjuvants for eliciting antiviral neutralizing antibody and T cell responses.
With the generous support of the National Institute of Allergy and Infectious Diseases and the Cystic Fibrosis Foundation, I founded my own subgroup within Pentelute lab space in early 2023. In addition to direct extensions of the work described above, project areas to be covered by this subgroup in the near future include studies on the selective activation of peptidomimetics, LL-37 potentiation of gram-positive antibiotics for combinatorial therapy, structure-activity relationships of selected defensins, and initial extensions from gram-negative bacteria into the realm of mycobacteria. I will further continue my clinical work within the MGH Mycobacterial Center and incorporate aspects of this into my basic research on therapeutic development.
My career aspiration is to become an independent physician-scientist working at the intersection of protein engineering, omics technologies, and infectious diseases for the development and characterization of novel antimicrobial agents and vaccines. In practical terms, this means developing robust and flexible technologies that can be deployed both in my lab and in others around the world to confront a wide variety of challenges in infectious diseases as global needs and local interests dictate.
Friday, September 27, 2024
10:15 AM – 11:45 AM ET