Small cyclic sodium channel inhibitors.
Small cyclic sodium channel inhibitors.
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DOI：
10.1016/j.bcp.2020.114291
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发表时间：
2021-01
影响因子：
5.8
通讯作者：
Tytgat, Jan
中科院分区：
文献类型：
--
作者：
Peigneur, Steve;Oliveira, Cristina da Costa;de Sousa Fonseca, Flavia Cristina;McMahon, Kirsten L.;Mueller, Alexander;Cheneval, Olivier;Nogueira Freitas, Ana Cristina;Starobova, Hana;Gama Duarte, Igor Dimitri;Craik, David J.;Vetter, Irina;de Lima, Maria Elena;Schroeder, Christina I.;Tytgat, Jan
电压门控钠（NaV）通道在一系列（病理）生理过程中起关键作用。在大量证据表明NaV通道亚型NaV1.7-NaV1.9参与伤害感受之后，在制药工业中产生了许多兴趣来追求这些通道作为镇痛靶标。最近，NaV1.1、NaV1.3和NaV1.6也被确定参与疼痛通路。从蜘蛛和锥螺中分离的毒液衍生的富含二硫键的肽毒素已被广泛用作探针来研究这些通道，并作为药物先导引起了人们的极大兴趣。然而，由于不利的生理化学属性，包括体内药代动力学差和口服生物利用度有限，很少有基于肽的先导化合物作为药物。目前的工作旨在通过将这些较大的毒液衍生的NaV抑制剂缩小为更小、更“药物样”的分子，来弥合药物先导物和药物候选物之间的开发管道中的差距。在这里，我们使用小环肽的分子工程来帮助确定是什么驱动了这些缩小的抑制剂在NaV亚型中的亚型选择性和分子相互作用。我们设计了一系列小的，稳定的和新颖的NaV探针，其在体外显示NaV亚型选择性和效力，并结合有效的体内镇痛活性，涉及除NaV亚型调节之外的尚待阐明的镇痛途径。
Voltage-gated sodium (NaV) channels play crucial roles in a range of (patho)physiological processes. Much interest has arisen within the pharmaceutical industry to pursue these channels as analgesic targets following overwhelming evidence that NaV channel subtypes NaV1.7–NaV1.9 are involved in nociception. More recently, NaV1.1, NaV1.3 and NaV1.6 have also been identified to be involved in pain pathways. Venom-derived disulfide-rich peptide toxins, isolated from spiders and cone snails, have been used extensively as probes to investigate these channels and have attracted much interest as drug leads. However, few peptide-based leads have made it as drugs due to unfavourable physiochemical attributes including poor in vivo pharmacokinetics and limited oral bioavailability. The present work aims to bridge the gap in the development pipeline between drug leads and drug candidates by downsizing these larger venom-derived NaV inhibitors into smaller, more “drug-like” molecules. Here, we use molecular engineering of small cyclic peptides to aid in the determination of what drives subtype selectivity and molecular interactions of these downsized inhibitors across NaV subtypes. We designed a series of small, stable and novel NaV probes displaying NaV subtype selectivity and potency in vitro coupled with potent in vivo analgesic activity, involving yet to be elucidated analgesic pathways in addition to NaV subtype modulation.
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影响因子：
5.4
作者：
French RJ;Yoshikami D;Sheets MF;Olivera BM
通讯作者：
Olivera BM
影响因子：
64.8
作者：
Bhardwaj, Gaurav;Mulligan, Vikram Khipple;Bahl, Christopher D.;Gilmore, Jason M.;Harvey, Peta J.;Cheneval, Olivier;Buchko, Garry W.;Pulavarti, Surya V. S. R. K.;Kaas, Quentin;Eletsky, Alexander;Huang, Po-Ssu;Johnsen, William A.;Greisen, Per Jr;Rocklin, Gabriel J.;Song, Yifan;Linsky, Thomas W.;Watkins, Andrew;Rettie, Stephen A.;Xu, Xianzhong;Carter, Lauren P.;Bonneau, Richard;Olson, James M.;Coutsias, Evangelos;Correnti, Colin E.;Szyperski, Thomas;Craik, David J.;Baker, David
通讯作者：
Baker, David
DOI：
10.1523/jneurosci.3795-08.2008
发表时间：
2008-12-24
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Binshtok AM;Wang H;Zimmermann K;Amaya F;Vardeh D;Shi L;Brenner GJ;Ji RR;Bean BP;Woolf CJ;Samad TA
通讯作者：
Samad TA
影响因子：
2.5
作者：
Khasar, SG;Gold, MS;Levine, JD
通讯作者：
Levine, JD
影响因子：
7.3
作者：
Markgraf, Rene;Leipold, Enrico;Heinemann, Stefan H.
通讯作者：
Heinemann, Stefan H.