dalazatide (ShK-186) / KPI Therap, TuHURA Bio - LARVOL DELTA

KV1.3 REGULATES MACROPHAGE IMMUNE FUNCTION THROUGH THE PI3K/AKT PATHWAY TO ALLEVIATE METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS (AASLD 2025) - "In vitro, an inflammatory model was constructed using LPS-stimulated RAW264.7 macrophages, and cells were treated with the Kv1.3 inhibitor ShK-186 to assess inflammatory cytokine (IL-6, TNF-α) production and migratory capacity... This study is the first to demonstrate that Kv1.3 regulates macrophage inflammatory response and migration via the PI3K/AKT signaling pathway, thereby influencing MASH progression. Hepatic knockdown of Kv1.3 significantly improves MASH-related pathological features, supporting Kv1.3 as a potential therapeutic target for MASH."

Hepatology • Inflammation • Liver Failure • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • IL6 • TNFA

KCNE4-dependent modulation of Kv1.3 pharmacology. (PubMed, Biochem Pharmacol) - "Kv1.3 blockers are effective in treating multiple sclerosis (fampridine) and psoriasis (dalazatide). Various leukocyte types expressing different Kv1.3/KCNE4 configurations participate in the immune response. Our data provide evidence that the presence of these variable architectures, which affect both the structure of the complex and their pharmacology, should be considered when developing putative therapeutic approaches."

Journal • CNS Disorders • Dermatology • Immunology • Inflammation • Multiple Sclerosis • Psoriasis

Structure-function relationships in ShKT domain peptides: ShKT-Ts1 from the sea anemone Telmatactis stephensoni. (PubMed, Proteins) - "ShK is a potent blocker of voltage-gated potassium channels (K 1.x), and an analog, ShK-186 (dalazatide), has completed Phase 1 clinical trials in plaque psoriasis. We show that either a buried dyad that does not become exposed during MD simulations, or a partially exposed dyad that becomes buried during MD simulations, correlates with weak or absent activity against K 1.x channels. Therefore, structure determination coupled with MD simulations, may be used to predict whether new sequences belonging to the ShKT family may act as potassium channel blockers."

Journal • Dermatology • Immunology • Psoriasis

Structure of the voltage-gated potassium channel K1.3: Insights into the inactivated conformation and binding to therapeutic leads. (PubMed, Channels (Austin)) - "Binding of the peptide dalazatide (ShK-186) and an antibody-ShK fusion to the external vestibule of K1.3 narrows and stabilizes the selectivity filter in the open-conducting conformation, although K efflux is blocked by the peptide occluding the pore through the interaction of ShK-Lys22 with the backbone carbonyl of K1.3-Tyr447 in the selectivity filter...Binding of the anti-K1.3 nanobody A0194009G09 to the turret and residues in the external loops of the voltage-sensing domain enhances the dilation of the outer selectivity filter in an exaggerated inactivated conformation. These studies lay the foundation to further define the mechanism of slow inactivation in K channels and can help guide the development of future K1.3-targeted immuno-therapeutics."

IO biomarker • Journal • Review • Immunology • Inflammation

Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with Granulomatosis with polyangiitis. (PubMed, Rheumatology (Oxford)) - "Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects."

Journal • Immunology • Infectious Disease • Novel Coronavirus Disease • Rare Diseases • Vasculitis • CD4 • IFNG • IL17A • IL21 • IL4 • TNFA

Mechanisms Underlying C-type Inactivation in Kv Channels: Lessons From Structures of Human Kv1.3 and Fly Shaker-IR Channels. (PubMed, Front Pharmacol) - "Such a reversal, at least partially, is induced by the peptide dalazatide...However, the intra-subunit bond that fastens the filter to the pore-helix is absent, suggesting an incomplete reversal of the process. These mechanisms define how Kv channels self-regulate the flow of K by changing the conformation of the selectivity filter."

Journal • Review

Rearrangement of a unique Kv1.3 selectivity filter conformation upon binding of a drug. (PubMed, Proc Natl Acad Sci U S A) - "In dalazatide-Kv1.3, binding of dalazatide to the channel's outer vestibule narrows the selectivity filter, Y447 occupies a position seen in other K channels, and this conformation is stabilized by a network of intersubunit hydrogen bonds. These remarkable rearrangements in the selectivity filter underlie Kv1.3's transition into the drug-blocked state."

Journal • Immune Modulation • Inflammation

The Kv1.3 K channel in the immune system and its "precision pharmacology" using peptide toxins. (PubMed, Biol Futur) - "To date, the highest affinity Kv1.3 inhibitors with the best Kv1.3 selectivity are the engineered analogues of the sea anemone peptide ShK (e.g., ShK-186), the engineered scorpion toxin HsTx1[R14A] and the natural scorpion toxin Vm24...Despite the significant progress in the field of Kv1.3 molecular pharmacology several progressive questions remain to be elucidated and discussed here. These include the conjugation of the peptides to carriers to increase the residency time of the peptides in the circulation (e.g., PEGylation and engineering the peptides into antibodies), use of rational drug design to create novel peptide inhibitors and understanding the potential off-target effects of Kv1.3 inhibition."

Journal • Review • CNS Disorders • Immunology • Multiple Sclerosis

Discovery of K 1.3 ion channel inhibitors: Medicinal chemistry approaches and challenges. (PubMed, Med Res Rev) - "Selectivity of dalatazide (ShK-186), a synthetic derivate of the sea anemone toxin ShK, was achieved by chemical modification and has successfully reached clinical trials as a potential therapeutic for treating autoimmune diseases...Some small-molecule inhibitors with well-defined structure-activity relationships have been optimized for selective delivery to mitochondria, and these offer therapeutic potential for the treatment of cancers. This overview of K 1.3 inhibitors and methodologies is designed to provide a good starting point for drug discovery to identify novel effective K 1.3 modulators against this target in the future."

Journal • Review • CNS Disorders • Complement-mediated Rare Disorders • Contact Dermatitis • Dermatitis • Dermatology • Diabetes • Immunology • Inflammatory Arthritis • Metabolic Disorders • Multiple Sclerosis • Myasthenia Gravis • Oncology • Psoriasis • Rheumatoid Arthritis • Rheumatology • Type 1 Diabetes Mellitus

The voltage-gated potassium channel K1.3 as a therapeutic target for venom-derived peptides. (PubMed, Biochem Pharmacol) - "Moreover, an analogue of the sea anemone peptide ShK (known as dalazatide) has successfully completed Phase 1 clinical trials in mild-to-moderate plaque psoriasis...Venom-derived peptides that have been reported recently to target K1.3 are also described. The increasing number of autoimmune and other conditions in which K1.3 is upregulated and is therefore a potential therapeutic target, combined with the fact that many venom-derived peptides are potent inhibitors of K1.3, suggests that venoms are likely to continue to serve as a rich source of new pharmacological tools and therapeutic leads targeting this channel."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dermatology • Dermatopathology • Fibrosis • Gastroenterology • Gene Therapies • Immunology • Inflammatory Bowel Disease • Movement Disorders • Multiple Sclerosis • Parkinson's Disease • Psoriasis • Psoriatic Arthritis • Rheumatoid Arthritis • Rheumatology

Kineta adds to its pipeline of venom-derived drug candidates, in-licenses conotoxin program for non-narcotic pain relief (Businesswire) - "ShK-186 is Kineta's lead clinical stage autoimmune drug candidate...its ability to suppress self-reactive inflammatory processes in autoimmune diseases...Kineta obtained development rights and has advanced ShK-186 into Phase 1 human clinical trials."

Pipeline update • Lupus • Multiple Sclerosis • Rheumatoid Arthritis

Durable pharmacological responses from the peptide drug ShK-186, a specific Kv1.3 channel inhibitor that suppresses T cell mediators of autoimmune disease (J Pharmacol Exp Ther) - In delayed-type hypersensitivity, chronic relapsing-remitting experimental autoimmune encephalomyelitis & pristane-induced arthritis rat models, a single dose of ShK-186 every 2-5 days was as effective as daily administration; ShK-186's slow distribution from the injection site & its long residence time on the Kv1.3 channel contribute to the prolonged therapeutic effect of ShK-186 in animal models of autoimmune disease

Preclinical-animal • Rheumatoid Arthritis

Kv1.3 Channel as a Key Therapeutic Target for Neuroinflammatory Diseases: State of the Art and Beyond. (PubMed, Front Neurosci) - "One of the synthetic analogs ShK-186, being developed as a therapeutic for autoimmune diseases, has successfully completed first-in-man Phase 1 trials. In addition to addressing the recent progress on the studies underlying the pharmacological characterizations of ShK on MS, the review will also explore the possibility for clinical treatment of ShK-like Kv1.3 blocking polypeptides on other neuroinflammatory diseases."

Journal • Review

Cnidarian peptide neurotoxins: a new source of various ion channel modulators or blockers against central nervous systems disease. (PubMed, Drug Discov Today) - "Although marine resources offer thousands of possible peptides, only one peptide derived from Cnidaria: ShK-186, also named dalazatide, has reached the pharmaceutical market. This review focuses on neuroprotective agents derived from cnidarian neurotoxic peptides."

Journal • Review