Biology subjects

Lee, S.-D.

Publications and source records attributed to Lee, S.-D..

3 recordsLinked to original sources

bioRxiv2026

A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology

The ATP-gated P2X7 receptor (P2X7R) activates inflammatory signaling pathways in the central nervous system. In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimers disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-{beta} plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.

neuroscience↗

bioRxiv2025

UB-MBX-46 is a potent and selective antagonist of the human P2X7 receptor developed by structure-based drug design

The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Interspecies variation among existing antagonists has proven challenging, in part due to the dearth of molecular information on different receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with new and existing structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with picomolar potency and high selectivity, revealing its significant therapeutic potential.

biochemistry↗

bioRxiv2020

Classic articles in Apoptotic Research: A Bibliometric Analysis

BackgroundClassic articles are defined as research papers with a total citation of one thousand or more. The present study is to identify and analyse the characteristics of the classic articles in apoptosis research. MethodClassic articles with total of 1,000 or more citations from Web of Science Core Collection since year of publication to the end of 2017 were basically assessed regarding their document types, languages, journals, and Web of Science categories within 1900 to 2017. ResultThe study showed 418 classic documents in apoptotic research including 260 articles published between 1972 and 2012. The most productive Web of Science category was multidisciplinary sciences. Nature published most of these classic articles followed by Cell, and Science. The most productive country and institution were United States and Harvard University respectively. The author S.J. Korsmeyer from Harvard University was the most productive in apoptosis field and published 13 classic apoptosis articles while the author J.C Reed had more potential to publish classic apoptosis articles in future. The author J.C. Reed and V.A. Fadok had equal potential to publish the same number of classic articles as first- and corresponding-author. Article of Kerr et al. in 1972 was the most popular and cited apoptosis article. The most impact article in 2017 was article entitled "Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion" by Dong et al. in 2002. ConclusionThis study seems to identify the most industrious authors, institutions, and countries in the field of apoptosis research. It also tends to reveal the historical and discoveries related to the pathophysiology of apoptosis as well as the most impact publications on apoptosis studies.

cell biology↗