[SARM1] A Neurology Target of Growing Importance in Drug Discovery

SARM1 (Sterile Alpha and TIR Motif Containing 1) has emerged as one of the most relevant molecular targets in neurology-focused drug discovery. Its importance comes from its central role in programmed axon degeneration, a process now recognized as a major driver of neurodegenerative, neuroinflammatory, and injury-related disorders.

When activated, SARM1 rapidly depletes axonal NAD+, leading to energy failure, axonal breakdown, and ultimately neuron damage. Because of this, inhibiting SARM1 is increasingly seen as a promising strategy to preserve axons, even when the underlying disease cannot yet be fully reversed.

In several animal models of neurodegeneration, loss of SARM1 activity has shown neuroprotective effects, making this enzyme a highly attractive target for drug discovery.

• SARM1 is a central driver of axon degeneration, making it a high-value target in neurological drug discovery
• It plays a role across ALS, Parkinson’s, MS, neuropathies, and CNS injuries
• Measuring SARM1 activity is critical for inhibitor screening and validation
• Two main assay approaches exist:
  • Hydrolase activity (classical, robust)
  • Base exchange activity (more sensitive, optimized)
• Choosing the right assay depends on your sensitivity, throughput, and workflow needs

What is SARM1?

SARM1 belongs to the Toll/Interleukin receptor-1 (TIR1) family and functions as both:

• an ADP-ribosyl cyclase
• a NAD glycohydrolase

Its TIR domain displays NADase activity, cleaving NAD+ into:

• ADP-ribose (ADPR)
• cyclic ADPR
• nicotinamide

SARM1 is associated with mitochondria and can act as a sensor of metabolic stress. It is highly expressed in neurons, where its activation causes depletion of axonal NAD+ and drives pathological axon loss.

Importantly, mutations in the SARM1 gene leading to constitutive NADase activity have been identified in patients with ALS. Conversely, reduced or absent SARM1 activity can protect neurons and may help limit axonal degeneration.

Why SARM1 is relevant across multiple neurological diseases?

Because axonal degeneration is a shared pathological mechanism, SARM1 has become relevant in a wide range of disorders.

Key disease areas linked to SARM1

• Peripheral neuropathies
  Including traumatic nerve injury, chemotherapy-induced neuropathy, and diabetic neuropathy
• Neurodegenerative diseases
  Including ALS, Parkinson’s disease, and potentially Alzheimer’s disease, where axonal loss is often an early event
• Multiple sclerosis and other neuroinflammatory diseases
  Where SARM1 may contribute to inflammation-driven axonal damage
• Traumatic brain injury and spinal cord injury
  Where SARM1 activation is a key driver of post-injury axon degeneration
• Inherited axonopathies
  Especially disorders involving NMNAT2 deficiency or other forms of metabolic stress that trigger SARM1 activation

Measuring SARM1 activity and inhibition

Given its growing pharmaceutical relevance, SARM1 has become an important target for compound screening and inhibitor profiling.

Our partner BPS Bioscience has developed assay solutions to measure:

• SARM1 enzymatic activity
• the inhibitory effect of compounds and drug candidates on SARM1

Two complementary assay principles are available.

1. SARM1 Fluorogenic Hydrolase Activity Assay

What the assay measures?

This SARM1 Fluorogenic Hydrolase Activity Assay is designed to quantify NAD+ cleavage activity in screening and profiling applications. It is available in convenient 96-well and 384-well formats, making it suitable for a range of throughput needs.

Etheno-NAD is initially non-fluorescent because of internal quenching. When SARM1 cleaves the substrate and releases nicotinamide, fluorescence increases in direct proportion to enzymatic activity.

Fig. 1: Assay principle
Source: BPS Bioscience

Example inhibitor data

SARM1 activity was measured in the presence of increasing concentrations of DSRM-3716, a well-characterized SARM1 inhibitor. Results were expressed as percentage activity relative to the positive control.

Using this assay, the IC50 of DSRM-3716 was determined to be 15 µM.

Fig. 2: SARM1 inhibition by DSRM-3716 measured with the 96-well kit format
Source: BPS Bioscience

2. SARM1 Inhibition Base Exchange Activity Assay

What makes this assay different?

This SARM1 Inhibition Base Exchange Activity Assay uses a different measurement principle and offers a more sensitive approach to assessing SARM1 inhibition.

As a result, fluorescence intensity at 520 nm increases proportionally with SARM1 activity.

Fig. 3: Base exchange assay principle
Source: BPS Bioscience / adapted from Li W. et al., 2021, eLife 10:e67381

Example inhibitor data

Using this assay format, the IC50 of DSRM-3716 was determined to be 0.3 µM.

This suggests that the SARM1 Inhibition Base Exchange Activity Assay enables a more sensitive measurement of SARM1 inhibitors than the classical SARM1 Fluorogenic Hydrolase Activity Assay kit.

Fig. 4: SARM1 inhibition by DSRM-3716 measured with the
SARM1 Inhibition Base Exchange Activity Assay
Source: BPS Bioscience

Which SARM1 assay should you choose?

Supporting your SARM1 drug discovery workflow

As SARM1 becomes an increasingly important target in neurology-related research, selecting the right assay format is essential for generating reliable and decision-ready data.

Whether your goal is to:

• measure SARM1 enzymatic activity
• screen inhibitor candidates
• compare compound potency
• optimize assay robustness, there are now state-of-the-art assay options available to support your work.

• References

  
  Article content created by Tebubio using courtesy materials provided by BPS Bioscience.