Single Residue Substitutions That Confer Voltage-Gated Sodium Ion Channel Subtype Selectivity in the NaV1.7 Inhibitory Peptide GpTx-1

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• 作者：Justin K. Murray ; Jason Long ; Anruo Zou ; Joseph Ligutti ; Kristin L. Andrews ; Leszek Poppe ; Kaustav Biswas ; Bryan D. Moyer ; Stefan I. McDonough ; Les P. Miranda
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：March 24, 2016
• 年：2016
• 卷：59
• 期：6
• 页码：2704-2717
• 全文大小：708K
• ISSN：1520-4804

文摘

There is interest in the identification and optimization of new molecular entities selectively targeting ion channels of therapeutic relevance. Peptide toxins represent a rich source of pharmacology for ion channels, and we recently reported GpTx-1 analogs that inhibit Na_V1.7, a voltage-gated sodium ion channel that is a compelling target for improved treatment of pain. Here we utilize multi-attribute positional scan (MAPS) analoging, combining high-throughput synthesis and electrophysiology, to interrogate the interaction of GpTx-1 with Na_V1.7 and related Na_V subtypes. After one round of MAPS analoging, we found novel substitutions at multiple residue positions not previously identified, specifically glutamic acid at positions 10 or 11 or lysine at position 18, that produce peptides with single digit nanomolar potency on Na_V1.7 and 500-fold selectivity against off-target sodium channels. Docking studies with a Na_V1.7 homology model and peptide NMR structure generated a model consistent with the key potency and selectivity modifications mapped in this work.