Peptide‑potassium channel interaction law-guided design of Kv1.3 channel-selective peptide immunosuppressants

The human Kv1.3 (hKv1.3) channel is an attractive therapeutic target for T cell-mediated autoimmune diseases. However, the development of hKv1.3-selective peptide immunosuppressants remains challenging due to the limited exploitation of structural differences between hKv1.3 and other potassium channels. Using the scorpion toxin BmKTX as a template, we applied peptide-potassium channel interaction principles to engineer BmKTX-derived peptides by modulating the distribution of acidic residues. This approach led to the identification of a highly hKv1.3-selective peptide, ADIP-6 (BmKTX-K6D/D19K/D33K), which effectively exploits differential structural features between hKv1.3 and other potassium channels. ADIP-6 inhibited the hKv1.3 channel with an IC₅₀ of 0.8 ± 0.1 nM. Notably, at 1 μM, ADIP-6 exhibited minimal inhibitory effects on other human potassium channels. Functionally, ADIP-6 significantly suppressed IL-2 production in Jurkat cells, reduced delayed-type hypersensitivity responses, and alleviated disease severity in a rat model of experimental autoimmune encephalomyelitis (EAE). In summary, we rationally designed a highly selective hKv1.3 channel-targeting immunosuppressant, ADIP-6, providing a general strategy for developing selective hKv1.3 blockers through negatively charged residue scanning based on peptide-potassium channel interaction principles.