LTGO-33 is a novel NaV1.8 inhibitor with a unique mechanism of action

Voltage-gated sodium channels (NaVs) have consistently been a focal point of scientific interest due to their integral role in neuronal excitability and pain transmission. Among these, NaV1.8 (SCN10A), a channel specifically expressed in peripheral nociceptors, has emerged as a compelling target for novel analgesic development. Gain-of-function mutations in SCN10A are associated with increased pain sensation in small-fiber neuropathy, diabetic peripheral neuropathy, and trigeminal neuralgia. Pharmacologic inhibition of NaV1.8 is now clinically validated as a novel analgesic mechanism of action targeting the PNS for both acute and chronic pain (see VX-150, VX-548 from Vertex).

In a recent paper on LTGO-33, a novel NaV1.8 inhibitor, scientists from Latigo Biotherapeutics present findings that could reshape our approach to pain modulation. Employing electrophysiological assays (both manual and automated patch clamp, including Nanion’s SyncroPatch 384), the study revealed LTGO-33’s nanomolar efficacy and a remarkable 600-fold selectivity for NaV1.8 over other human NaV isoforms. A notable aspect of LTGO-33 is its state-independent inhibition mechanism, distinguishing it from previous inhibitors that primarily targeted the inactivated state of the channel.

Chimeric constructs and site-directed mutagenesis pinpointed the interaction site of LTGO-33, identifying the extracellular cleft of the second voltage-sensing domain (VSDII) as its action locus. This novel binding site contrasts with the traditional pore region targeted by other inhibitors and highlights LTGO-33’s unique pharmacological action. Biophysical mechanism of action studies demonstrated that LTGO-33 stabilized the deactivated state of VSDII, effectively keeping the channel closed by preventing the movement of VSDII.

The study also uncovered the species specificity of LTGO-33, effective in human and non-human primates but less so in canine and rodent models. This finding underscores the importance of model selection in pre-clinical pain studies.

Importantly, LTGO-33 was able to effectively block rare gain-of-function NaV1.8 variants that have been identified in patients with painful neuropathies, including diabetic peripheral neuropathy and small-fiber neuropathy, suggesting that selective NaV1.8 inhibition could provide relief for both general pain disorders and genetically driven pain.

In conclusion, LTGO-33’s introduction of a novel pharmacologic paradigm in targeting NaV1.8 is significant. Its unique binding site and mechanism of action suggest potential for developing analgesics with increased specificity and reduced off-target effects, crucial for avoiding complications in cardiac, respiratory, and CNS functions.

Find the original article here: Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action

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