During　the　long-term　evolution　of　animal　toxins　acting　on　potassium　channels,　the　acidic　residues　can　orientate　the　toxin　binding　interfaces　by　adjusting　the　molecular　polarity.　Based　on　the　evolutionary　function　of　toxin　acidic　residues,　de　novo　peptide　drugs　with　distinct　binding　interfaces　were　designed　for　the　immunotherapeutic　target,　the　Kv1.3　channel.　Using　a　natural　basic　toxin,　BmKTX,　as　a　template,　which　contains　2　acidic　residues　(Asp19　and　Asp33),　we　engineered　two　new　peptides　BmKTX-19　with　1　acidic　residue　(Asp33),　and　BmKTX-196　with　2　acidic　residues　(Asp6　and　Asp33)　through　only　adjusting　acidic　residue　distribution　for　reorientation　of　BmKTX　binding　interface.　Pharmacological　experiments　indicated　that　BmKTX-19　and　BmKTX-196　peptides　were　specific　inhibitors　of　the　Kv1.3　channel　and　effectively　suppressed　cytokine　secretion.　In　addition　to　the　structural　similarity　between　the　designed　and　native　peptides,　both　experimental　alanine-scanning　mutagenesis　and　computational　simulation　further　indicated　that　the　binding　interface　of　wild-type　BmKTX　was　successfully　reoriented　in　BmKTX-19　and　BmKTX-196,　which　adopted　distinct　toxin　surfaces　as　binding　interfaces.　Together,　these　findings　indicate　not　only　the　promising　prospect　of　BmKTX-19　and　BmKTX-196　as　drug　candidates　but　also　the　desirable　feasibility　of　the　evolution-guided　peptide　drug　design　for　discovering　numerous　peptide　drugs　for　the　Kv1.3　channel.