Martina Piga
| Targeting NaV and HV1 channels: discovery of novel small-molecule inhibitors |
| Martina Piga1, Nace Zidar1, Tihomir Tomašič1 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia |
| Abstract Voltage-gated ion channels are essential transmembrane proteins that regulate key physiological processes, including neuronal excitability, muscle contraction, and pH homeostasis. Their dysfunction is implicated in numerous diseases, such as chronic pain, epilepsy, cardiovascular disorders, and cancer, making them attractive targets for drug discovery. This work focuses on the design, synthesis, and biological evaluation of novel inhibitors targeting voltage-gated sodium (NaV) and proton (HV1) channels [1]. The first part of the study focused on the NaV1.3 isoform, which is upregulated following nerve injury and associated with neuronal hyperexcitability [2]. Using structure-based drug design, two series of arylsulfonamide derivatives were developed with the aim of improving physicochemical properties while maintaining high potency. Electrophysiological evaluation using automated patch-clamp techniques identified several compounds with nanomolar activity. These inhibitors displayed state-dependent behavior, preferentially targeting the inactivated state of the channel. Importantly, selectivity profiling revealed a favorable safety profile, with several lead compounds showing no activity against the cardiac NaV1.5 isoform. The second part of the research addressed the discovery of novel HV1 inhibitors through computer-aided drug design. HV1 channels are key regulators of intracellular pH and are frequently overexpressed in highly metastatic cancer cells [3].Virtual screening and molecular docking led to the identification of a new class of inhibitors with a 5-phenyl-2-aminoimidazole scaffold. Subsequent structure–activity relationship (SAR) studies enabled the optimization of analogues with low micromolar IC50 values and improved drug-like properties. Notably, biological evaluation demonstrated a correlation between HV1 inhibition and antiproliferative activity in cancer cell lines overexpressing the channel, supporting their potential as anticancer agents. Finally, selectivity profiling and ligand-based pharmacophore modeling were employed to investigate isoform specificity and guide the identification of new NaV1.7 inhibitors for chronic pain treatment. While achieving selectivity remains challenging, the developed models demonstrated potential in virtual screening campaigns, identifying novel candidate molecules for further validation. Overall, this work contributes to the understanding of ion channel modulation and provides novel chemical tools for the study of NaV and HV1 channels. The results validate the integration of computational design and synthetic chemistry in discovering potent inhibitors, offering promising candidates for the treatment of chronic pain and cancer. |
| References [1] Bagal SK, Brown AD, Cox PJ, et al (2013) Ion Channels as Therapeutic Targets: A Drug Discovery Perspective. J Med Chem 56:593–624. https://doi.org/10.1021/jm3011433. [2] Liao S, Liu T, Yang R, et al (2023) Structure and Function of Sodium Channel Nav1.3 in Neurological Disorders. Cell Mol Neurobiol 43:575–584. https://doi.org/10.1007/s10571-022-01211-w. [3] Chaves G, Jardin C, Derst C, Musset B (2023) Voltage-Gated Proton Channels in the Tree of Life. Biomolecules 13:1035. https://doi.org/10.3390/biom13071035. |