Vertex Pharmaceuticals has developed an innovative pain treatment drug, VX-548, also known as suzetrigine. Targeting Nav1.8, a voltage-gated sodium channel crucial in transmitting pain signals, VX-548 demonstrates high selectivity for Nav1.8. This specificity could potentially provide superior analgesic effects compared to opioid drugs, while avoiding addiction and other side effects.
VX-548 stands to become the first new drug for treating acute and neuropathic pain in over two decades, representing a significant breakthrough in pain management. Meanwhile, the global race to develop Nav1.8 inhibitors is heating up. Chinese pharmaceutical company Hengrui Pharma is also advancing its own Nav1.8 inhibitor, showcasing China's rapid progress in this field. Vertex's extensive portfolio in pain treatment, including both Nav1.8 and Nav1.7 inhibitors, highlights its commitment and ambition to lead in this therapeutic area.
Study Background
In our in vitro studies, VX-548 demonstrated high selectivity and efficacy in targeting Nav1.8 channels using manual patch-clamp assays. These assays included evaluations in both resting and half-inactivated states, providing comprehensive insights into the drug's performance.
Resting State: In the resting state, the sodium channel is closed and ready to be activated. This state is significant because it reflects the condition of the channel before any stimuli or action potentials occur. Evaluating drug effects in the resting state helps understand how the drug interacts with the channel under normal, unstimulated conditions.
Half-inactivated State: In the half-inactivated state, the sodium channel is partially inactivated, reflecting a condition where the channel has been subjected to prolonged or repeated stimulation and has not fully recovered. This state is critical for understanding how the drug affects the channel under conditions of sustained or repetitive activity, which is common in chronic pain conditions.
Importance of State-Dependent Assays: Conducting assays in both states is essential because sodium channels exhibit different conformations and properties depending on their state. Drugs might have varying efficacy and binding characteristics depending on whether the channel is in a resting or inactivated state.
State-Dependent Inhibition and Sodium Channel Isoform Selectivity of VX-548 on hNaV1.8
Nav1.8-Resting State: IC50: 0.2067 nM HillSlope: 0.8284
Nav1.8-Half-inactivated State: IC50: 0.3187 nM HillSlope: 0.9237
Our data indicates VX-548's potent inhibition of Nav1.8 channels, with minimal off-target effects on other sodium channels, as shown below:
Sodium Channel Inhibition at 10μM:
Nav1.1: 16.91% ± 1.87%
Nav1.2: 17.71% ± 2.54%
Nav1.3: 13.19% ± 0.92%
Nav1.4: 32.79% ± 3.01%
Nav1.5: 17.13% ± 1.36%
Nav1.6: 6.32% ± 2.91%
Nav1.7: 10.16% ± 1.72%
Comparative Selectivity of VX-548 for Human and Rat Nav1.8
Human vs. Rat Nav1.8:
Human: TP1-IC50: 0.2067 nM TP2-IC50: 0.3187 nM
Rat: TP1-IC50: 14.88 nM TP2-IC50: 22.30 nM
These results underscore VX-548's superior selectivity and potency in human Nav1.8 channels compared to rat models, reinforcing its potential in clinical settings.
Effect of VX-548 on Rat DRG Action Potential
Our studies also examined the impact of VX-548 on rat dorsal root ganglion (DRG) neurons' action potentials. VX-548 effectively inhibited action potentials in rat DRG neurons, which are crucial for pain signal transmission. The concentration-dependent effects showed a significant reduction in the frequency and amplitude of action potentials at various concentrations of VX-548.
Key Findings:
√ At 10 nM concentration, VX-548 reduced the action potential frequency significantly.
√ Higher concentrations led to a more pronounced inhibition, indicating a strong dose-response relationship.
√ VX-548's inhibition of action potentials in DRG neurons suggests its potential effectiveness in reducing pain signaling at the source.
Conclusion
VX-548 represents a major advancement in pain management, with significant potential to address acute and neuropathic pain without the risks associated with opioids. To learn more about how our Nav1.8 blocker screening services can support your drug development programs, please contact ICE Bioscience.
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2024-08-26
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