Recent advances in the pharmacology of voltage-gated ion channels

Voltage-gated ion channels (VGICs) are critical regulators of membrane potential, cellular excitability, and calcium signaling in both excitable and nonexcitable tissues and constitute important drug targets for neurological, cardiovascular, and immunological diseases. This review describes recent progress in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels, highlighting clinical-stage compounds, emerging therapeutic modalities, and new strategies in VGIC drug discovery, emphasizing the increasingly central role of protein structures and artificial intelligence. Several compounds targeting VGICs have progressed to clinical trials for epilepsy, atrial fibrillation, psoriasis, and difficult-to-treat disorders, such as chronic pain, schizophrenia, major depression, and amyotrophic lateral sclerosis. The therapeutic landscape for VGIC-related disorders is expanding beyond traditional small molecules and antisense oligonucleotides and gene therapies targeting VGICs at the mRNA or gene level are currently in both early and late clinical trial stages for Dravet syndrome and developmental epileptic encephalopathy. The progression of such varied modalities suggests that the extensive efforts dedicated to elucidating VGIC biophysics and structure, coupled with rigorous target validation, are beginning to translate into therapeutic advancements. Furthermore, we discuss emerging discovery strategies, including the growing impact of VGIC structures, computational structural modeling, virtual screening of focused and ultralarge libraries, and artificial intelligence-driven redesign and de novo design of biologics. Although these approaches are poised to substantially accelerate the early stages of ion channel drug discovery, the clinical stages will continue to require careful selection of indications and thoughtful clinical trial design to fully realize the long-held potential of VGICs as drug targets. SIGNIFICANCE STATEMENT: Drug development for voltage-gated ion channels is widely considered to be challenging. This article reviews recent advances in the pharmacology of voltage-gated Na⁺, voltage-gated Ca²⁺, and voltage-gated K⁺ channels by examining compounds currently in clinical trials, including emerging new therapeutic approaches such as antisense oligonucleotides and gene therapy. We then discuss noteworthy recent developments, including the increasing availability and impact of ion channel structures, structural modeling, virtual screening, and artificial intelligence-assisted protein design, which are likely to accelerate the early stages of ion channel drug discovery. Success of the later stages will continue to rely on rigorous target validation, and proper choices of clinical candidates and clinical trial design.