The Kritzer Laboratory
The goal of the Kritzer lab is to discover novel bioactive molecules and to use them to understand the molecular biology of human disease.
As we achieve a molecular-level understanding of disease, we are left with the daunting task of developing molecules to intervene. The Kritzer laboratory aims to (1) discover molecules that can be used to probe the mechanisms of human disease and (2) to streamline the development of those molecules as therapeutic agents.We apply innovative methods that integrate genetics, biophysics, and organic synthesis in order to bypass the biases, expense, and specialized nature of traditional high-throughput screening.
Selections with genetically encoded cyclic peptide libraries
We use genetically encoded libraries of macrocyclic peptides to select bioactive molecules in models of human disease. This new technology uses genetics to generate large libraries of cyclic peptides in living cells and to screen millions of these compounds in a single day for those that target specific proteins of interest.
Screening with synthetic libraries of peptide mimetics
Peptide mimetics have some of the properties of peptides, but are only accessible synthetically; thus, they bridge the gap between cyclic peptides and small molecules. We are synthesizing focused libraries of peptide mimetics and using high-efficiency, non-robotic screening methods to isolate molecules that bind target proteins. These approaches will yield novel, drug-like molecules that act via underexplored mechanisms such as inhibition of protein-protein interactions.
Peptide drug development
Synthetic methodology for optimizing peptide drugs has been established for isolated cases, but there remains a great need for systematic studies on the effects of various substitutions on molecular structure, function, and bioavailability. By starting with a diverse set of bioactive cyclic peptides, we will be able to generate uniform data describing the effects of peptide bond isosteres and other modifications. Focusing on cyclic peptides as a starting point also integrates this research area with the previous two, forming a continuous pipeline from molecule discovery through synthetic optimization and testing in disease models.
The hallmarks of these strategies are efficiency and accessibility, ensuring rapid molecule discovery and characterization as well as the ability to address drug targets that might be deemed intractable or too risky for more traditional approaches.