Tarantula venom peptide Tl1a inhibits pain-channel NaV1.8 with 8-fold selectivity over other sodium channels | Research

The takeaway

Spider venom peptide Tl1a from Thrixopelma longicolli inhibits the pain-relevant NaV1.8 channel at IC50 210 nM with 6-8x selectivity over other NaV subtypes, with loop 4 hydrophobicity critical for activity via domain IV S3-S4 interaction.

210 nM NaV1.8 inhibition
Tarantula peptide Tl1a targets the same pain channel (NaV1.8) as the newly approved drug suzetrigine, with structure-activity insights for improved drug design

What the researchers found

Tl1a: 36 amino acids from T. longicolli. NaV1.8 IC50=210 nM. 8x selective over NaV1.4 (1769 nM), NaV1.1 (2201 nM). 6x over NaV1.7 (1278 nM). Similar at NaV1.5 (282 nM), KV2.1 (156 nM). Loop 4 hydrophobicity critical. Domain IV S3-S4 interaction site.

Why it matters

NaV1.8 is the target of the recently approved pain drug suzetrigine. Understanding how venom peptides interact with NaV1.8 provides templates for designing more selective pain drugs.

How the study worked

Solid-phase peptide synthesis. Automated whole-cell patch-clamp electrophysiology. Multiple NaV and KV channel subtypes. Loop 4 analogue structure-activity studies.

What this study cannot tell us

In vitro electrophysiology only. NaV1.5 (cardiac) potency raises safety concerns. No pain model testing. Loop 4 modifications reduced NaV1.8 activity rather than improving it.

How to read the evidence

Rigorous electrophysiology with structure-activity analysis. Strong for drug design but no in vivo data.

When this study was published

Published in 2025.

The bigger picture

Venom peptides that selectively target pain-relevant sodium channels are natural prototypes for non-opioid analgesics. Tl1a's NaV1.8 activity and the structure-activity insights guide rational drug design for the post-opioid era.

Questions still open

Can Tl1a selectivity for NaV1.8 over NaV1.5 be improved?
Would intrathecal delivery avoid cardiac NaV1.5 effects?
Is the domain IV S3-S4 interaction a common target for NaV1.8 modulators?

Common questions

Can tarantula venom be used for pain treatment?

Not directly, but this tarantula venom peptide (Tl1a) blocks NaV1.8—the same pain channel targeted by the recently approved drug suzetrigine. Understanding how the venom peptide works helps scientists design better pain drugs that are more selective and effective.

Why is NaV1.8 important for pain?

NaV1.8 is a sodium channel found specifically on pain-sensing nerve fibers. Blocking it can reduce pain without affecting other body functions. Spider venoms have evolved peptides that selectively target these channels, providing natural templates for non-addictive pain medications.

Read the original research

A hydrophobic loop of the spider-venom peptide Tl1a drives activity at NaV1.8.

European journal of pharmacology, 1001, 177751

View on PubMed ↗Publisher’s paper ↗

Citation

Thapa, Ashvriya; Tran, Hue; Ragnarsson, Lotten; Keramidas, Angelo; Herzig, Volker; Brinkwirth, Nina; Deuis, Jennifer R; Vetter, Irina. (2025). A hydrophobic loop of the spider-venom peptide Tl1a drives activity at NaV1.8.. European journal of pharmacology, 1001, 177751. https://doi.org/10.1016/j.ejphar.2025.177751