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Therapeutic lead

ThsB Thoeris as a structural probe for antiviral NAD⁺-hydrolase pathways (SARM1 parallel)

ThsB, the TIR sensor of the Thoeris system, hydrolyzes NAD⁺ upon phage infection — the same mechanism as human SARM1, the only TIR-domain NAD⁺-hydrolase in vertebrates. Using ThsB as an evolutionary template to identify allosteric modulators of SARM1 relevant to antiviral defense and neuroinflammation.

Content

Starting intuition

Thoeris is one of the best-characterized anti-phage systems structurally among those discovered by Doron et al. (Science 2018). Its sensor ThsB contains a TIR domain — and during phage infection, this domain hydrolyzes NAD⁺ to trigger altruistic cell death.

This mechanism is functionally identical to that of SARM1 (Sterile Alpha and TIR Motif containing 1), the only TIR-domain NAD⁺-hydrolase identified in vertebrates. SARM1 regulates axonal degeneration and participates in innate antiviral immunity: its activation in neurons during viral infection may contribute to neuroinflammation, and its inhibition is being studied in the context of axonal injury and neurotropic infections (West Nile, Zika).

This evolutionary parallel is remarkable: the same TIR-NAD⁺-hydrolase architecture has been conserved from bacteria to vertebrates to signal a genomic threat and orchestrate a sacrificial response.

Hypothesis

The functional conservation between ThsB and SARM1 is deep enough that compounds identified as modulators of ThsB NAD⁺-hydrolase activity may show cross-activity on human SARM1. ThsB, being structurally simpler and more experimentally accessible than SARM1 (no SAM domain, smaller structure), constitutes a screenable proxy for identifying initial chemical scaffolds.

The ultimate biological target is SARM1 in two contexts:

  • Neurotropic antivirals: inhibit SARM1 activation to limit neuroinflammation in Zika/West Nile/SARS-CoV-2 (long COVID) infections
  • Neuroprotection: limit axonal degeneration induced by SARM1 activation during infection-associated nerve injury

Key experimental questions

  1. Structural conservation: Align ThsB (AlphaFold structures available, accession P0CU62) against experimental crystal structures of human SARM1 (PDB 7LCU, 7MK3). Identify conserved catalytic residues and differences in allosteric pockets.

  2. Pocket divergence: Are there allosteric sites on ThsB absent from SARM1, and vice versa? The specificity of a modulator depends on this divergence.

  3. Substrate profile: Do ThsB and SARM1 share the same range of NAD⁺/NAD⁺ analog substrates, or do they show divergent preferences that would limit chemical transferability?

  4. Activation vs inhibition: Is the target strategy to inhibit SARM1 (neuroprotection) or to potentiate ThsB (model bacterial defense)? Both have distinct biological justifications.

Limitations and risks

  • TIR-to-TIR conservation is partial: not all TIR domains are NAD⁺-hydrolases. ThsA and ThsB are atypical even among bacterial TIRs. The structural transferability should not be overestimated.

  • SARM1 has a complex pleiotropic role: its inhibition must be temporal and tissue-specific. A systemic chronic inhibitor would likely affect NAD⁺ homeostasis in non-neuronal cells. Only local formulations (intrathecal) or conditional activators would be clinically relevant.

  • ThsB is activated by a bacterial second messenger (an isomer of 3’,3’-cGAMP) that has no direct equivalent in human cells. ThsB activation mechanism therefore differs from SARM1 allosteric activation (by PKC, calcium, etc.), limiting the analogy at the mechanistic level of activation.

V1 family Thoeris (high translational priority, NAD⁺ sensor-effector system). Reference: Doron et al. (Science 2018, DOI 10.1126/science.aar4120). Aligned with NS-2 (assessable hypotheses on Bactaegion) and linking to J3 (real contribution via Bernheim 2026 data).

Peer review

Local evaluation panel. Gesture e of the engagement report.

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