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

被引：12

作者：

Adams, Gregory L. ^{[1
]}

Pall, Parul S. ^{[1
]}

Grauer, Steven M. ^{[1
]}

Zhou, Xiaoping ^{[1
]}

Ballard, Jeanine E. ^{[1
]}

Vavrek, Marissa ^{[1
]}

Kraus, Richard L. ^{[1
]}

Morissette, Pierre ^{[1
]}

Li, Nianyu ^{[1
]}

Colarusso, Stefania ^{[2
]}

Bianchi, Elisabetta ^{[2
]}

Palani, Anandan ^{[3
]}

Klein, Rebecca ^{[1
]}

John, Christopher T. ^{[1
]}

Wang, Deping ^{[1
]}

Tudor, Matthew ^{[1
]}

Nolting, Andrew F. ^{[1
]}

Biba, Mirlinda ^{[4
]}

Nowak, Timothy ^{[3
]}

Makarov, Alexey A. ^{[4
]}

Reibarkh, Mikhail ^{[4
]}

Buevich, Alexei, V ^{[3
]}

Zhong, Wendy ^{[4
]}

Regalado, Erik L. ^{[4
]}

Wang, Xiao ^{[4
]}

Gao, Qi ^{[4
]}

Shahripour, Aurash ^{[1
]}

Zhu, Yuping ^{[3
]}

de Simone, Daniele ^{[2
]}

Frattarelli, Tommaso ^{[2
]}

Pasquini, Nicolo' Maria ^{[2
]}

Magotti, Paola ^{[2
,5
]}

Iaccarino, Roberto ^{[2
]}

Li, Yuxing ^{[1
]}

Solly, Kelli ^{[1
]}

Lee, Keun-Joong ^{[4
]}

Wang, Weixun ^{[1
]}

Chen, Feifei ^{[1
]}

Zeng, Haoyu ^{[1
]}

Wang, Jixin ^{[1
]}

Regan, Hilary ^{[1
]}

Amin, Rupesh P. ^{[1
]}

Regan, Christopher P. ^{[1
]}

Burgey, Christopher S. ^{[1
]}

Henze, Darrell A. ^{[1
]}

Sun, Chengzao ^{[1
,6
]}

Tellers, David M. ^{[1
]}

机构：

[1] Merck & Co Inc, West Point, PA 19486 USA

[2] IRBM Spa, Peptides & Small Mol R&D Dept, I-00071 Pomezia, RM, Italy

[3] Merck & Co Inc, Kenilworth, NJ 07033 USA

[4] Merck & Co Inc, Rahway, NJ 07065 USA

[5] Gubra ApS, Horsholm Kongevej 11B, DK-2970 Horsholm, Denmark

[6] Janssen Res & Dev, Mailstop 42-2512A,1400 McKean Rd, Spring House, PA 19477 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 01期

关键词：

GATED SODIUM-CHANNELS; LIPID-BILAYERS; VOLTAGE SENSOR; SPIDER PEPTIDE; HUWENTOXIN-IV; ION CHANNELS; INHIBITION; SUBTYPE; ACTIVATION; ZICONOTIDE;

D O I：

10.1021/acs.jmedchem.1c01570

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 Na(v)1.7, 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.

引用

页码：485 / 496

页数：12

共 53 条

[1]

Adams GL, 2017, RSC DRUG DISCOV, V59, P411

[2] Manipulation of a spider peptide toxin alters its affinity for lipid bilayers and potency and selectivity for voltage-gated sodium channel subtype 1.7 [J].