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DOI 10.1021/acs.jmedchem.1c01570

Медицинская библиотека · Journal of medicinal chemistry · 2021

Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain.

Adams Gregory L, Pall Parul S, Grauer Steven M, Zhou Xiaoping, Ballard Jeanine E, Vavrek Marissa, Kraus Richard L, Morissette Pierre, Li Nianyu, Colarusso Stefania, Bianchi Elisabetta, Palani Anandan, Klein Rebecca, John Christopher T, Wang Deping, Tudor Matthew, Nolting Andrew F, Biba Mirlinda, Nowak Timothy, Makarov Alexey A, Reibarkh Mikhail, Buevich Alexei V, Zhong Wendy, Regalado Erik L, Wang Xiao, Gao Qi, Shahripour Aurash, Zhu Yuping, de Simone Daniele, Frattarelli Tommaso, Pasquini Nicolo' Maria, Magotti Paola, Iaccarino Roberto, Li Yuxing, Solly Kelli, Lee Keun-Joong, Wang Weixun, Chen Feifei, Zeng Haoyu, Wang Jixin, Regan Hilary, Amin Rupesh P, Regan Christopher P, Burgey Christopher S, Henze Darrell A, Sun Chengzao, Tellers David M

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Аннотация

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.

Для цитирования: Adams Gregory L, Pall Parul S, Grauer Steven M, Zhou Xiaoping, Ballard Jeanine E, Vavrek Marissa, Kraus Richard L, Morissette Pierre, Li Nianyu, Colarusso Stefania, Bianchi Elisabetta, Palani Anandan, Klein Rebecca, John Christopher T, Wang Deping, Tudor Matthew, Nolting Andrew F, Biba Mirlinda, Nowak Timothy, Makarov Alexey A, Reibarkh Mikhail, Buevich Alexei V, Zhong Wendy, Regalado Erik L, Wang Xiao, Gao Qi, Shahripour Aurash, Zhu Yuping, de Simone Daniele, Frattarelli Tommaso, Pasquini Nicolo' Maria, Magotti Paola, Iaccarino Roberto, Li Yuxing, Solly Kelli, Lee Keun-Joong, Wang Weixun, Chen Feifei, Zeng Haoyu, Wang Jixin, Regan Hilary, Amin Rupesh P, Regan Christopher P, Burgey Christopher S, Henze Darrell A, Sun Chengzao, Tellers David M. Development of ProTx-II Analogues as Highly Selective Peptide Blockers of Nav1.7 for the Treatment of Pain.. Journal of medicinal chemistry. 2021. DOI: 10.1021/acs.jmedchem.1c01570.

Предметные рубрики MeSH

AnimalsCell DegranulationCystineDrug DesignHot TemperatureMast CellsModels, MolecularNAV1.7 Voltage-Gated Sodium ChannelPainPain MeasurementRatsSodium Channel BlockersSpider Venoms
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