Mechanism of Action
Kv1.3 Channel Blockade and T Cell Suppression
Kv1.3 channels maintain the negative resting membrane potential of T cells required for sustained calcium influx during T cell activation. Blocking Kv1.3 with ShK or dalazatide hyperpolarizes TEM cells, prevents calcium influx, and inhibits their activation and cytokine secretion without affecting naive T cells or other immune cell populations that express alternative potassium channels (Kv1.5, KCa3.1). This selectivity for TEM cells is the basis for the immunosuppressive action with a proposed narrow therapeutic window compared to broad immunosuppressants.
Kv1.3 vs Kv1.1 Selectivity Engineering
Native ShK blocks Kv1.1 (expressed in neurons and peripheral nervous system) with similar potency to Kv1.3, raising potential neurological side effects. ShK-186 incorporates an N-terminal aminoethylphosphonomethylphenylalanine (Aep) extension and a 4-phosphoTyr substitution to achieve 100-fold improved selectivity for Kv1.3 over Kv1.1, reducing CNS liability. This engineering illustrates rational selectivity optimization in ion channel-targeting peptide therapeutics.
Research Summary
Psoriasis Phase 2
Phase 2 (Completed)Dalazatide (ShK-186) completed a Phase 2a trial in plaque psoriasis (n=23). Subcutaneous injection twice weekly for 4 weeks showed significant reduction in skin lesion area and plaque severity scores compared to placebo. The trial validated the Kv1.3 target in human autoimmune disease. Kineta Inc. developed dalazatide and demonstrated favorable safety profile in this study, with the primary concern being injection site reactions.
Multiple Sclerosis and Rheumatoid Arthritis
Preclinical/Early PhaseAnimal models of MS (EAE, experimental autoimmune encephalomyelitis) and RA show significant disease reduction with ShK or dalazatide treatment. The rationale is strong because TEM cells are elevated in these diseases. Phase 1 safety studies in MS patients showed the expected Kv1.3 pharmacodynamic effects (reduced TEM cell activation) at tolerated doses, though full Phase 2 efficacy trials have not been completed.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Psoriasis (clinical trial) | 30-300 ug SC twice weekly | Twice weekly x 4 weeks | Subcutaneous injection |
| Kv1.3 in vitro assay | 10-100 pM | Continuous exposure | Patch clamp assay |
Dalazatide is an investigational drug. Clinical dosing from Phase 2a psoriasis trial.
Interactions
Safety Profile
Dalazatide was well tolerated in Phase 2 with injection site reactions as the primary adverse event. No significant CNS effects observed at clinical doses despite Kv1.1 expression in neurons, supporting the engineered selectivity. Potential concerns include impaired immune surveillance if Kv1.3 blockade is too deep. Therapeutic window appears reasonable based on Phase 2 data.
References
- [1]Pennington MW, et al. (1995). Chemical synthesis and characterization of ShK toxin: a potent potassium channel inhibitor from a sea anemone. Int J Pept Protein Res, 46(5), 354-358.
- [2]Tarcha EJ, et al. (2017). Safety and pharmacodynamics of dalazatide, a Kv1.3 channel inhibitor, in the treatment of plaque psoriasis: a randomized phase 2a trial. PLoS One, 12(7), e0180762.