Robin Polt
Professor
The University of Arizona
Talk Information
Peptide Therapeutics from Discovery to the Clinic
17 June 2025, 11:35am - 11:50am, in the Pacific Jewel Ballroom
L32 – O-Linked Glycopeptides Derived from Endogenous Neurotransmitters as a Source of Brain-Penetrant CNS Drugs for the Treatment of Stroke, mTBI and Neurodegeneration
Professor Robin Polt serves as a Professor in the Department of Chemistry and Biochemistry at the University of Arizona. He is also affiliated with the BIO5 Institute, the Neuroscience Graduate Interdisciplinary Program, and the Department of Pharmacology and Toxicology. His research focuses on the design and synthesis of glycopeptide drugs derived from endogenous neurotransmitters, aiming to develop therapeutics capable of crossing the blood-brain barrier to treat neurological disorders.
Academic Background
Dr. Polt began his academic journey at Indiana University–Purdue University Indianapolis, IUPUI, where he contributed to the development of the “O’Donnell Schiff base” method for synthesizing unusual amino acids. He earned his Ph.D. in Organic Chemistry from Columbia University under the mentorship of Professor Gilbert Stork and completed postdoctoral training with Professor Dieter Seebach at ETH Zürich. Since joining the University of Arizona in 1988, he has been instrumental in advancing the field of bioorganic chemistry.
Research Focus
Professor Polt's laboratory specializes in the synthesis of glycopeptides and glycolipids, exploring their roles in cell signaling and membrane biology. His team has developed glycosylated analogs of neuropeptides such as enkephalins, oxytocin, and angiotensin, enhancing their stability and ability to penetrate the central nervous system. These efforts aim to create novel therapeutics for conditions like Parkinson’s disease and post-surgical cognitive dysfunction.
Notable Contributions
Dr. Polt has significantly contributed to the understanding of glycopeptide structure and function, leading to the development of drug candidates that can cross the blood-brain barrier. His work has resulted in the creation of glycopeptide-based neurotransmitters with in vivo efficacy, and he has been involved in the discovery of biologically active sphingomyelins and glycosides in insects. His research has been supported by agencies such as the NSF, NIH, and the Michael J. Fox Foundation.
Professional Engagements
Beyond his research, Professor Polt is actively involved in mentoring students and has guided numerous undergraduate and graduate researchers, many of whom have pursued advanced degrees at prestigious institutions. He has also contributed to the commercialization of his research through startups like Teleport Pharmaceuticals and has served as a Specialty Chief Editor for the journal Frontiers in Drug Discovery, focusing on neurological drugs.
Through his innovative research and dedication to education, Professor Robin Polt continues to make significant contributions to the fields of chemical biology and neuropharmacology.
L49
O-Linked Glycopeptides Derived from Endogenous Neurotransmitters as a Source of Brain-Penetrant CNS Drugs for the Treatment of Stroke, mTBI and Neurodegeneration
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona, USA; Tulane University School of Medicine; The Uniform Services University Hospital
Our studies with glycopeptides suggest that two conformational macrostates exist—(1) a large water-soluble ensemble of structures (random coil state), and (2) a much smaller amphipathic ensemble that is membrane bound. Most endogenous neuropeptides possess amphipathic character, which constrains them to the membrane compartment. Pioneering studies with enkephalins and endorphin/dynorphin analogues suggested that modulation of membrane affinity by glycosylation (or other water-soluble moieties) produces “biousian glycopeptides” that are systemically available and can cross the BBB.
Membranes are critical for peptide transport and binding events. The role of the membrane in transport is generally that of a barrier, but the role of the membrane in receptor binding is an enabling one. Schwyzer’s “membrane compartment theory” can be useful in understanding the dynamics of peptide-receptor interactions. His contention is that the membrane should be viewed as an essential component in bringing together the receptor and ligand. Max Delbruck performed a theoretical study of receptor-ligand interactions in the context of membrane compartmentalization. He found that a 2D search for a receptor was much more efficient than a 3D search for a receptor, and suggested that the initial interaction was adsorption of the ligand to the membrane.
Our studies show that endogenous peptide neurotransmitters and hormones can be converted into glycopeptides related to enkephalin, endorphin, endomorphins, oxytocins, PACAP, and angiotensin1–7 for the treatment of pain, addiction, and neurological conditions such as mTBI, Stroke and neurological issues. One glycopeptide, PNA51 has now begun clinical studies for the treatment of vascular dementia.
1. Bernard K, Mota JA, et al. Exp. Neurol. 2024, 381, 114926.