Event

Our research program focuses on the development of exquisite chemical tools which offer unprecedented opportunities for elucidating protein structure, dynamics, and function in living systems. Complementary to genetic and biochemical tools, covalent modification of proteins with designed chemical probes in vivo provides a versatile strategy in probing protein function in their native habitats with potentially improved spatial and temporal resolution. A key challenge in this area, which is our primary interest, is the development of bioorthogonal reactions that enable the performance of highly selective chemical modification of proteins in living systems. By employing insights gained from organic chemistry literature, we have been developing the photoinduced 1,3-dipolar cycloaddition reactions (“photoclick chemistry”) involving small-ring heterocycles and simple alkenes for both in vitro and live-cell applications. Some aspects of this effort include the synthesis of small-ring heterocycles, the measurement of their reactivity in biological media through kinetic analysis, and the elucidation of possibly novel reaction mechanisms. Through collaboration, the genetic incorporation of these bioorthogonal groups into proteins in living systems is also being pursued in an effort to study the dynamics of protein posttranslational modifications such as lipidation and phosphorylation.
A second interest in Lin’s group focuses on the design of cell-permeable, sidechain cross-linked (“stapled”) peptide helices as anti-cancer therapeutics. Peptide helices mediate many important protein-protein interactions regulating various cellular processes in cancers. However, peptides are poor drug candidates for intracellular targets such as protein-protein interactions due to their poor metabolic stability and membrane permeability. By applying the bioorthogonal reaction developed in our lab, we found that “stapled” peptides can be efficiently synthesized with good yields and also exhibit reinforced helical structures and improved membrane permeability. In collaboration with cancer biologists, we are extending this strategy to prepare the biologically active, stapled peptides targeting the p53-Mdm2/Mdmx and BH3-Bcl2/Bcl-xL interactions, respectively, and evaluating their anticancer activities against tumor cells as well as in nude mice models.

An integrated approach combining synthetic and physical organic chemistry, protein biochemistry, molecular and cell biology, and modern instrumental analyses is employed in our investigations. Students participating in our research program are expected to develop strong.

Carol Fritsch
Email: cfritsch@buffalo.edu
Phone: 645-2842