jm1c01570_si_001.pdf (12.51 MB)
Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain
journal contribution
posted on 2021-12-21, 16:10 authored by Gregory L. Adams, Parul S. Pall, Steven M. Grauer, Xiaoping Zhou, Jeanine E. Ballard, Marissa Vavrek, Richard L. Kraus, Pierre Morissette, Nianyu Li, Stefania Colarusso, Elisabetta Bianchi, Anandan Palani, Rebecca Klein, Christopher T. John, Deping Wang, Matthew Tudor, Andrew F. 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, Roberto 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. TellersInhibitor 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.
