Talk Session: SESSION 6: PEPTIDE LIBRARIES, ARRAYS AND PROTEOMICS
Date: Monday, June 13, 2022
Talk Time: 01:35 pm - 02:00 pm
Talk Title: DiaCyt: A Platform Technology for the Discovery of Molecular Transport Systems for Delivery to the Central Nervous System
Kathlynn Brown, earned her Ph.D. in organic chemistry at the University of Texas at Austin, during which time she received fellowships from the Mahler Memorial Foundation and the Organic Division of the American Chemical Society. She continued her training at the University of California at San Francisco, where she was a Damon Runyon Walter Winchell Postdoctoral Fellow.
Brown began her independent career at UT Southwestern Medical Center and moved to SRI International to expand her translational research. She has utilized her multidisciplinary expertise in organic chemistry, peptide chemistry, biochemistry, and molecular biology to address challenges in biomedical research.
Her laboratory was among the first to adopt cell-based biopanning of phage-displayed peptide libraries. Using this approach, she has developed a suite of high-affinity peptides that target a variety of different cell types. Brown has co-authored numerous peer-reviewed papers, three reviews, and one book chapter in this area.
Brown’s research team is developing peptides that target tumors for use as delivery vehicles for drugs, nanoparticles, and toxins. They are also utilizing the peptides to develop novel immunotherapies to fight cancer. Additionally, the peptides are being utilized as molecular imaging agents for diagnosis and classification of cancers.
The Brown Laboratory focuses on probing protein-protein and protein-peptide interactions and developing methods to manipulate these macromolecular complexes. In particular, the laboratory is interested in interactions that occur at the cell surface and how these interactions dictate underlying biology of the cell. The surface of a cell represents a collection of macromolecules, which provides cells with a unique cellular landscape specific to the type and state of the cell. Ligands that discriminate between subtle differences in cell surface phenotypes have utility in a wide variety of research and clinical applications. In particular, cell binding ligands that can deliver biologically active “cargo” to a specific cell type or a diseased cell are highly sought.
Toward the goal of isolating cell targeting ligands, the Brown Laboratory utilizes phage display panning protocols to identify peptides that mediate binding and uptake into cells. The laboratory has identified cell-targeting peptides for more than 40 different cell types, and is expanding this number.
The blood brain barrier, BBB, is a set of specialized and highly selective cellular barriers that protects the central nervous system, CNS. While necessary under normal physiology, the BBB prevents entry of many neurotherapeutics into the brain and biologic therapies such as antibodies and gene therapies are essentially excluded from the CNS.
We have developed an unbiased screening platform to identify peptides that mediate delivery throughout the CNS without disruption of the BBB or destruction of biological cargo. This approach, which we have named DiaCyt – Dia for Through, and Cyt for Cell – utilizes high diversity phage-displayed peptide libraries to identify peptides that transport cargos.
We have identified three peptides as lead candidates. The synthetic peptides mediate transport of a protein in an in vitro model with efficiencies of 8-20%. Tight junctions remain intact during peptide transport. Upon intravenous injection into a rat, each peptide is transported into the CNS and is distributed throughout the ventricular system and within the surrounding parenchyma. Transport efficiency is enhanced 3-11-fold into the CSF and 0-22-fold into the brain.
We have also identified cell specific peptides to microglia and neuronal cells, capable of intracellular delivery of cargos. Combining these different peptides allows for both transport and cell specific targeting within the CNS.