Dr. Damla Sürmeli, Tufts University
“Bass, Treble, and Volume: Tuning Multi-Receptor Agonism Using Chemistry”
Abstract
Peptide therapeutics bridge the gap between small molecules and biologics, offering high potency and selectivity. Since the introduction of the first therapeutic peptide, insulin, peptides have been recognized as a viable option. A recent example showcasing their potential is glucagon-like peptide-1 (GLP-1). Released from the gut upon food ingestion, GLP-1 stimulates glucose-dependent insulin secretion, called the incretin effect. Along with restoring normoglycemia, it also suppresses appetite while delaying gastric emptying, both contributing to weight loss. GLP-1 analogues have become blockbuster drugs as they maintain glucose homeostasis and regulate satiety signaling to the extent that they are deemed as the first-line therapy for the treatment of type 2 diabetes (T2D) prior to insulin. Despite its effectiveness, GLP-1 is vulnerable to rapid inactivation by a ubiquitous serine protease called dipeptidyl peptidase-4 (DPP4). Our laboratory has implemented a unique N-alkylation approach that maintains full activity at its cognate receptor, GLP-1 receptor (GLP-1R), while simultaneously resisting enzyme-mediated degradation involving functionalities varying in size, shape, charge, polarity, and stereochemistry. Building on our GLP-1 results, we expanded our work to other peptides, driven by the current emphasis on unimolecular chimeric therapies where combining GLP-1 with other peptide hormones, like glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon, enhances therapeutic potential. Initially, we observed altered potencies among mono-agonists of GLP-1, GIP, and glucagon with the same N-terminal alkylation. Subsequently, we applied promising N-alkylation moieties to multi-receptor ligands, which enabled us to fine-tune receptor activity. As interest in multi-receptor agonists grows, N-terminal alkylation not only provides DPP4 protection but also aids in achieving optimal receptor selectivity without altering the peptide sequence.
Dr. Damla Surmeli recently completed her PhD in Chemistry at Tufts University under the supervision of Prof. Krishna Kumar. Her doctoral research focused on designing, synthesizing, and characterizing peptide hormone libraries with N-terminal alkylations to explore the chemical space within receptor binding pockets and investigate the factors influencing receptor signaling. She received her BSc in Chemistry from Bilkent University, where she gained valuable research experience in Dr. Yunus Emre Turkmen’s group, focusing on the total synthesis of fungal natural products containing benzo[j] fluoranthene ring skeletons. She is now excited to begin her new role as a medicinal chemist at Parabilis Medicines in Cambridge, MA, where she will focus on synthesizing peptide-based therapeutics for cancer treatment.
Date : November 12, 2024 Tuesday
Time : 12:30
Place : SBZ-14
All interested are cordially invited.