Scientists at the Icahn Institute of Medication at Mount Sinai have recognized the design of a unique carrier found in red platelets and how it collaborates with drugs. The findings were presented in greater detail in the September 7 issue of Nature Structural & Molecular Biology [DOI: 10.1038/s41594-023-01085-6], which could lead to the creation of medicines that are more specific.
It was discovered by the research team, which included Daniel Wacker, PhD, Bin Zhang, PhD, and Avner Schlessinger, PhD, that this transporter facilitates the movement of a substance known as bicarbonate, which can be inhibited by certain drugs. They devised novel compounds that are capable of achieving the same effect and discovered how these drugs block the transporter.
Despite being involved in numerous aspects of human physiology, including pH regulation, which involves keeping the level of acidity within a specific range, human bicarbonate transporters were previously poorly understood.
Utilizing cryo-electron microscopy, the group distinguished high-goal structures uncovering bicarbonate and inhibitor restricting, and their effect on the vehicle instrument. The researchers used computer simulations to examine millions of compounds that might interact with the substrate binding site with these new insights.
An innovative class of chemical inhibitors for anion exchanger 1, a protein that is essential for blood and red blood cell function, was discovered through their experiments.
“Our concentrate likewise shows the potential for growing new inhibitors with clinical potential for other solute transporter (SLC) proteins, a protein family acquiring significance in drug improvement,” says co-creator Dr. Zhang, the Willard T.C Johnson Exploration Teacher of Neurogenetics and Head of the Mount Sinai Community for Groundbreaking Sickness Displaying at Icahn Mount Sinai.
Then, the specialists intend to grow their examinations to other SLC proteins engaged with various issues including neurodegenerative infections, mental diseases, and disease.
Dr. Schlessinger, co-author and Associate Director of the Mount Sinai Center for Therapeutics Discovery at Icahn Mount Sinai, states, “This study effectively paves the way to using atomic-level insights toward the rapid development of promising drug-like molecules for SLC proteins.”
“Substrate binding and inhibition of the anion exchanger 1 transporter” is the title of the paper.
Michael J. Capper, PhD is one of the additional co-authors, all of whom collaborate with Icahn Mount Sinai unless otherwise noted; Shifan Yang, PhD; Stone, Alexander C.; Amgen’s Sezen Vatansever, MD, PhD; Gregory Zilberg, pursuing a PhD; Yamuna Kalyani Mathiharan, PhD; Raul Habib, (College of California, Berkeley);
Keino Hutchinson, PhD; Candidate for a PhD, Yihan Zhao; Dr. Mihaly Mezei; and Dr. Roman Osman.