![]() ![]() ![]() Namely, toxin acidic residues can guide the orientation of toxin binding interfaces. ![]() During the dominant electrostatic interactions between the positively charged binding interfaces of basic toxins and the negatively charged vestibule of the potassium channels 10, 18, 19, 20, 21, 22, these characteristically distributed acidic residues locate to the negatively charged non-binding interfaces of the basic toxins due to electrostatic repulsion forces between the acidic residues of both the toxins and potassium channels. In this work, a new evolution-guided drug design strategy was proposed based on the evolutionary function of toxin acidic residues, which can orient the toxin binding interfaces by adjusting the molecular polarity, which was illustrated in Fig. Despite the fact that the ShK-186 peptide blocks the Kv1.1 and Kv1.2 channels at nanomolar concentrations, clinical trial progress has greatly promoted the more extensive development of potent and selective Kv1.3 channel immunomodulators. Recently, the ShK-186 peptide, an analog of the anemone toxin peptide ShK, was identified as the first drug molecule to begin first-in-man phase-1 trials 11, 16. To further improve the selectivity of peptide candidates, some classical strategies were adopted, such as chemical modification of amino acid residues 13, sequence truncation 14, computer-aided design 10 and phage display libraries 15. Although these peptides show better selectivity towards the Kv1.3 channel than chemical molecules, they usually also inhibit some highly similar potassium channel subtypes 9, 10, 11, 12. To date, a large number of toxin peptides have been shown to inhibit the Kv1.3 channel at picomolar to nanomolar concentrations 9. Due to the inherent poor selectivity and potential side effects of previously reported chemical molecules targeting the Kv1.3 channel 4, 5, considerable attention has been paid to the discovery of peptide drugs recently.Äuring long-term molecular evolution, venoms from different species, such as scorpion, sea anemone, snake and cone snail, have become a well-known resource for peptide blockers that target the Kv1.3 channel 6, 7, 8. Kv1.3 channel blockers suppressed cytokine secretion and alleviated diseases in animal models of T cell-mediated autoimmune diseases 1, 3. The voltage-gated Kv1.3 potassium channel is expressed in effector memory T cells and has been proven to be an attractive drug target for the treatment of various autoimmune diseases 1, 2. 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. 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. Pharmacological experiments indicated that BmKTX-19 and BmKTX-196 peptides were specific inhibitors of the Kv1.3 channel and effectively suppressed cytokine secretion. 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. 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. 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. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |