Structural and Mechanistic Regulation of SARM1’s Transition from Autoinhibited to Neurotoxic State Published in CELL REPORTS

“SARM1 inhibitors have the potential to be widely applicable across a range of serious neurological diseases. We’re excited about the significant advances we have made towards elucidating SARM1 structure and mechanism of action,” said Shilpa Sambashivan, PhD, lead author and Vice President, Biology at Nura Bio. “Our team at Nura Bio has deployed an array of sophisticated tools to understand the large, multi-domain NAD hydrolase, SARM1 in its different functional states. Our structure-function studies provide the first glimpse into the molecular architecture of autoinhibited SARM1 and its transition to an activated pro-degenerative state, laying the foundation for potential SARM1-based neuroprotective therapies.”

Nura Bio’s initial focus is on preventing axonal degeneration, and the company is developing SARM1 inhibitors to prevent this early event and preserve neuronal integrity across many neurological diseases. The research results published in CELL REPORTS provide mechanistic insight into the tight regulation of SARM1’s activity by the local metabolite milieu and reaffirm SARM1’s role as a central switch in axon degeneration, driving axons from a latent phase to a catastrophic degenerative phase following injury.

“The scientific advances published in CELL REPORTS reflect Nura Bio’s commitment and progress in conducting groundbreaking science to support discovery of therapies that we hope will change the lives of people affected by neurodegenerative disease,” said Alpna Seth, PhD, President and CEO of Nura Bio. “These studies mark an important step in the mechanistic understanding of this critical neuronal pathway toward developing neuroprotective therapies that can act early in preventing or halting axonal degeneration, a hallmark of several diseases affecting central, peripheral or ocular nervous systems.”

For this research, the Nura Bio discovery team led by Dr. Sambashivan collaborated with the cryo-EM team led by Xiaochen Bai, PhD, at the University of Texas Southwestern Medical Center (UTSW).These studies build on work from the labs of Nura Bio co-founders Marc Freeman, PhD, Director of the Vollum Institute at the Oregon Health and Sciences University, and Steve McKnight, PhD, Distinguished Chair in Basic Biomedical Research in the Biochemistry Department at UTSW.

About Nura Bio

At Nura Bio, we envision a world where the diagnosis of a neurological disorder comes with the hope of a cure. Expanding on recent breakthroughs in crucial neurodegenerative pathways, we are positioned to deliver transformative neuroprotective therapies to prevent and protect against neuronal loss and related neuroimmune dysregulation. The company’s research and development strategy is currently centered on two approaches: prevention of neuronal loss to preserve neurological function; and restoring the function of the neuron-glia axis to improve the nervous system’s immune surveillance capacity in response to neurological injury. The company’s discovery engine and emerging multi-target pipeline spans these approaches and is well positioned to address a broad range of neurological diseases. Nura Bio’s lead program is the SARM1 inhibitor program. SARM1 has recently emerged as an axon-intrinsic metabolic sensor that is a pivotal driver of axonal degeneration and neuronal integrity. Axon degeneration is an early event in several neurological disorders, and halting it early has tremendous potential in the treatment of central, peripheral, and ocular neurological diseases.

For more information, visit www.nurabio.com.

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