Calcium-activated potassium (KCa) channels are ubiquitously expressed throughout the body and are able to regulate membrane potential and intracellular calcium concentrations, thereby playing key roles in cellular physiology and signal transmission. Consequently, it is unsurprising that KCa channels have been implicated in various diseases, making them potential targets for pharmaceutical interventions. Over the past two decades, numerous studies have been conducted to develop KCa channel-targeting drugs, including those for disorders of the central and peripheral nervous, cardiovascular, and urinary systems and for cancer. In this review, we synthesize recent findings regarding the structure and activating mechanisms of KCa channels. We also discuss the role of KCa channel modulators in therapeutic medicine. Finally, we identify the major reasons behind the delay in bringing these modulators to the pharmaceutical market and propose new strategies to promote their application.

Agrimonia pilosa Ledeb., an important medicinal herb in traditional East Asian medicine, is primarily used to treat abdominal pain, dysentery, and hemostasis. There are ten other reported species of Agrimonia plants, including Agrimonia coreana Nakai—a naturally growing species in South Korea—and Agrimonia eupatoria Linn. Although recent studies have isolated numerous active constituents and investigated their effects, the medicinal utility of this herb is not yet fully explored. Through patch-clamp recording, a previous study reported that Agrimonia plant extracts inhibit the function of Ca²⁺ release-activated Ca²⁺ channels (CRACs). Herein, we aimed to identify and isolate the main compounds in A. coreana responsible for CRAC inhibition while assessing the anti-inflammatory effects mediated by this inhibition. We demonstrated for the first time that alphitolic acid isolated from A. coreana has a dose-dependent inhibitory effect on CRAC activity and, thus, an inhibitory effect on intracellular calcium increase. Furthermore, analysis of human CD4⁺ T cell proliferation via the carboxyfluorescein diacetate succinimidyl ester method revealed that alphitolic acid inhibited T cell proliferation in a concentration-dependent manner. Our findings provide a theoretical basis for the potential therapeutic use of alphitolic acid in the treatment of inflammatory diseases.

RNA-dependent RNA polymerase (RdRP) represents a critical target for antiviral drug development. We developed a multi-model machine learning framework combining five traditional algorithms (ExtraTreesClassifier, RandomForestClassifier, LGBMClassifier, BernoulliNB, and BaggingClassifier) with a CNN deep learning model to identify potential RdRP inhibitors among FDA-approved drugs. Using the PubChem dataset AID 588519, our ensemble models achieved the highest performance with accuracy, ROC-AUC, and F1 scores higher than 0.70, while the CNN model demonstrated complementary predictive value with a specificity of 0.77 on external validation. Molecular docking studies with the norovirus RdRP (PDB: 4NRT) identified raloxifene as a promising candidate, with a binding affinity (−8.8 kcal/mol) comparable to the positive control (−9.2 kcal/mol). The molecular dynamics simulation confirmed stable binding with RMSD values of 0.12–0.15 nm for the protein–ligand complex and consistent hydrogen bonding patterns. Our findings suggest that raloxifene may possess RdRP inhibitory activity, providing a foundation for its experimental validation as a potential broad-spectrum antiviral agent.

Post-inflammatory hyperpigmentation (PIH) is a common pigmentary disorder characterized by excessive melanin production following skin inflammation. Histamine, a key inflammatory mediator, is known to stimulate melanogenesis via H₂ receptors; however, the underlying calcium (Ca²⁺) signaling mechanisms remain largely unexplored. In this study, we investigated the role of the ORAI1-STIM1 complex in histamine-induced melanogenesis using B16F10 melanoma cells and normal human epidermal melanocytes (NHEMs). Histamine (10–30 μM) significantly increased melanin content (2.5–2.8-fold), an effect specifically abolished by the H₂ antagonist famotidine. Notably, while acute histamine application failed to trigger immediate Ca²⁺ influx, chronic exposure significantly enhanced store-operated Ca²⁺ entry (SOCE) capacity by approximately 2.8-fold, providing evidence for a functional remodeling of the Ca²⁺ signaling machinery. Histamine-induced melanogenesis was significantly suppressed by intracellular Ca²⁺ chelation, pharmacological inhibition of ORAI1 (BTP-2 or Synta-66), and siRNA-mediated silencing of ORAI1 or STIM1, but not ORAI2, ORAI3, or STIM2. Our findings demonstrate that chronic histamine exposure drives hyperpigmentation through ORAI1-STIM1-mediated SOCE remodeling, establishing this complex as a promising therapeutic target for the treatment of PIH and related inflammatory pigmentary disorders.

Post-inflammatory hyperpigmentation (PIH) is a common pigmentary disorder characterized by excessive melanin production following skin inflammation. Histamine, a key inflammatory mediator, is known to stimulate melanogenesis via H2 receptors; however, the underlying calcium signaling mechanisms remain largely unexplored. In this study, we investigated the role of the ORAI1-STIM1 complex in histamine-induced melanogenesis using B16F10 melanoma cells and normal human epidermal melanocytes (NHEMs). Histamine (10–30 μM) significantly increased melanin content (2.5–2.8-fold), an effect specifically abolished by the H2 antagonist famotidine. Notably, while acute histamine application failed to trigger immediate calcium influx, chronic exposure significantly enhanced store-operated calcium entry (SOCE) capacity by approximately 2.8-fold, providing evidence for a functional remodeling of the Ca2+ signaling machinery. Histamine-induced melanogenesis was significantly suppressed by intracellular calcium chelation, pharmacological inhibition of ORAI1 (BTP-2 or Synta-66), and siRNA-mediated silencing of ORAI1 or STIM1, but not ORAI2, ORAI3, or STIM2. Our findings demonstrate that chronic histamine exposure drives hyperpigmentation through ORAI1-STIM1-mediated SOCE remodeling, establishing this complex as a promising therapeutic target for the treatment of PIH and related inflammatory pigmentary disorders.

The majority of disease-associated proteins are considered “undruggable” due to the absence of well-defined binding pockets, the presence of extended interaction surfaces, and intrinsic structural disorder, which collectively limit the effectiveness of conventional small molecules and biologics. Representative examples include KRAS, p53, and c-MYC. Peptide therapeutics, particularly macrocyclic peptides, occupy a unique chemical space capable of targeting such recalcitrant protein–protein interactions (PPIs) where small molecules often fail. However, traditional peptide discovery, which relies heavily on high-throughput screening, is labor-intensive and frequently yields candidates with suboptimal pharmacological properties. The integration of artificial intelligence has begun to transform peptide discovery from a largely empirical process into a rational and design-driven paradigm. Modern deep learning approaches, including diffusion-based generative models, enable the de novo design of peptide binders with high affinity and structural precision, even for disordered or previously intractable targets. In this perspective, we highlight key structural and biological challenges associated with undruggable proteins and consider how peptide-based modalities are beginning to overcome these longstanding barriers. We further explore how advances in artificial intelligence and computational modeling may reshape the rational design of next-generation peptide therapeutics and propose an integrated experimental–computational framework to facilitate the development of clinically actionable candidates.