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 methods that integrate genetics, biophysics, and organic synthesis to complement structure-based design and traditional high-throughput screening with innovative techniques.
Many of our targets are disease-associated proteins that have been ignored or discarded as "undruggable." By using new classes of molecules as inhibitors, we are reversing long-held assumptions about what proteins can be useful targets for cellular probes and potential therapies. We are currently targeting proteins involved in breast cancer, skin cancer, diabetes, bacterial meningitis, and bacterial pneumonia.
Getting in shape: Controlling peptide bioactivity and bioavailability using conformational constraints
Molecules can be successfully designed to inhibit a target protein by arraying specific functional groups in three dimensions in order to interact "just so" with the protein surface. Another tenet of drug design is that molecules must have favorable physicochemical properties that ensure it will be stable in biological systems and cell-penetrant. The Kritzer lab focuses on how molecule shape (its 3-D conformation) plays a predominant role in determining a molecule's chemical and biological function.
We are re-examining “exceptions” to physicochemical rules, and discovering surprisingly general scaffolds for highly bioactive and bioavailable molecules. We use novel design and combinatorial screening strategies to identify molecules that inhibit hard-to-target proteins involved in human disease, and then we are use conformation as a tool to improve the molecules' performance in biological systems. In this manner, we are producing not only inhibitors, but useful probes and therapeutic leads for targets that have been overlooked or abandoned as too difficult.
The hallmarks of our research strategies are efficiency, accessibility, and interdisciplinarity, covering a wide range of relevant science:
- Novel synthetic routes to useful building blocks for controlling peptide conformation
- Synthesis of novel constrained peptide scaffolds with unusual properties and improved cell penetration
- Structural characterization in order to develop design rules for constrained peptides
- Translation from test tube to cell culture to whole-organism models of disease
- Novel inhibitors of previously "undruggable" proteins