Bratkowski Matthew, Burdett Thomas C, Danao Jean, Wang Xidao, Mathur Prakhyat, Gu Weijing, Beckstead Jennifer A, Talreja Santosh, Yang Yu-San, Danko Gregory, Park Jae Hong, Walton Mary, Brown Sean P, Tegley Christopher M, Joseph Prem Raj B, Reynolds Charles H, Sambashivan Shilpa
Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA.
Chemistry Department, Nura Bio Inc., South San Francisco, CA 94080, USA.
Neuron. 2022 Nov 16;110(22):3711-3726.e16. doi: 10.1016/j.neuron.2022.08.017. Epub 2022 Sep 9.
Axon degeneration is an early pathological event in many neurological diseases. The identification of the nicotinamide adenine dinucleotide (NAD) hydrolase SARM1 as a central metabolic sensor and axon executioner presents an exciting opportunity to develop novel neuroprotective therapies that can prevent or halt the degenerative process, yet limited progress has been made on advancing efficacious inhibitors. We describe a class of NAD-dependent active-site SARM1 inhibitors that function by intercepting NAD hydrolysis and undergoing covalent conjugation with the reaction product adenosine diphosphate ribose (ADPR). The resulting small-molecule ADPR adducts are highly potent and confer compelling neuroprotection in preclinical models of neurological injury and disease, validating this mode of inhibition as a viable therapeutic strategy. Additionally, we show that the most potent inhibitor of CD38, a related NAD hydrolase, also functions by the same mechanism, further underscoring the broader applicability of this mechanism in developing therapies against this class of enzymes.
轴突退化是许多神经疾病早期的病理事件。烟酰胺腺嘌呤二核苷酸（NAD）水解酶SARM1被鉴定为一种核心代谢传感器和轴突执行者，这为开发能够预防或阻止退行性过程的新型神经保护疗法提供了一个令人兴奋的机会，但在推进有效的抑制剂方面进展有限。我们描述了一类依赖NAD的活性位点SARM1抑制剂，其作用机制是拦截NAD水解并与反应产物二磷酸腺苷核糖（ADPR）进行共价结合。由此产生的小分子ADPR加合物具有高效性，并在神经损伤和疾病的临床前模型中提供了令人信服的神经保护作用，证实了这种抑制模式是一种可行的治疗策略。此外，我们表明，相关的NAD水解酶CD38的最有效抑制剂也通过相同的机制发挥作用，进一步强调了该机制在开发针对这类酶的疗法中具有更广泛的适用性。
