2. Academic Validation
  3. Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease

Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease

  • Neuron. 2022 Sep 7;S0896-6273(22)00749-8. doi: 10.1016/j.neuron.2022.08.017.
Matthew Bratkowski 1,  Thomas C Burdett 1,  Jean Danao 1,  Xidao Wang 1,  Prakhyat Mathur 1,  Weijing Gu 1,  Jennifer A Beckstead 1,  Santosh Talreja 1,  Yu-San Yang 1,  Gregory Danko 1,  Jae Hong Park 1,  Mary Walton 2,  Sean P Brown 2,  Christopher M Tegley 2,  Prem Raj B Joseph 3,  Charles H Reynolds 4,  Shilpa Sambashivan 5
Affiliations

Affiliations

  • 1 Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA.
  • 2 Chemistry Department, Nura Bio Inc., South San Francisco, CA 94080, USA.
  • 3 WuXi AppTec, Research Services Division, 6 Cedarbrook Drive, Cranbury, NJ 08512, USA.
  • 4 Gfree Bio, 10601 FM 2222 Ste R PMB 206, Austin, TX 78730, USA.
  • 5 Biology Department, Nura Bio Inc., South San Francisco, CA 94080, USA. Electronic address: ssambashivan@nurabio.com.
PMID: 36087583 DOI: 10.1016/j.neuron.2022.08.017
Abstract

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.

Keywords

NAD hydrolase; SARM1; axon degeneration; neurodegenerative disease; neurofilament light; neuroprotection; small-molecule inhibitor; uncompetitive inhibition.

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