Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Na<sub>v</sub>1.7 for the Treatment of Pain
Gregory L. Adams, Parul S. Pall, Steven M. Grauer, Xiaoping Zhou, Jeanine Ballard, Marissa Vavrek, Richard L. Kraus, Pierre Morissette, Nianyu Li, Stefania Colarusso, Elisabetta Bianchi, Anandan Palani, Rebecca M. Klein, Christopher T. John, Deping Wang, Matthew Tudor, Andrew Nolting, Mirlinda Biba, Timothy Nowak, Alexey A. Makarov, Mikhail Reibarkh, Alexei V. Buevich, Wendy Zhong, Erik L. Regalado, Xiao Wang, Qi Gao, Aurash Shahripour, Yuping Zhu, Daniele De Simone, Tommaso Frattarelli, Nicolo’ Maria Pasquini, Paola Magotti, R. Iaccarino, Yuxing Li, Kelli Solly, Keun-Joong Lee, Weixun Wang, Feifei Chen, Haoyu Zeng, Jixin Wang, Hilary Regan, Rupesh P. Amin, Christopher P. Regan, Christopher S. Burgey, Darrell A. Henze, Chengzao Sun, David M. Tellers
Abstract
Inhibitor cystine knot peptides, derived from venom, have evolved to block ion channel function but are often toxic when dosed at pharmacologically relevant levels in vivo. The article describes the design of analogues of ProTx-II that safely display systemic in vivo blocking of Nav1.7, resulting in a latency of response to thermal stimuli in rodents. The new designs achieve a better in vivo profile by improving ion channel selectivity and limiting the ability of the peptides to cause mast cell degranulation. The design rationale, structural modeling, in vitro profiles, and rat tail flick outcomes are disclosed and discussed.