Targeting the CaVα-CaVβ interaction yields an antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy.
Targeting the CaVα-CaVβ interaction yields an antagonist of the N-type CaV2.2 channel with broad antinociceptive efficacy.
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靶向 CaV α-CaV β 相互作用产生具有广泛抗伤害功效的 N 型 CaV2.2 通道拮抗剂
DOI：
10.1097/j.pain.0000000000001524
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发表时间：
2019-07
期刊：
影响因子：
7.4
通讯作者：
Khanna M
中科院分区：
文献类型：
--
作者：
Khanna R;Yu J;Yang X;Moutal A;Chefdeville A;Gokhale V;Shuja Z;Chew LA;Bellampalli SS;Luo S;François-Moutal L;Serafini MJ;Ha T;Perez-Miller S;Park KD;Patwardhan AM;Streicher JM;Colecraft HM;Khanna M
抑制电压门控钙通道是治疗包括慢性疼痛在内的多种神经系统疾病的一种潜在方法。神经元CaV 1/CaV 2通道由α、β、γ和α2δ亚基组成。CaV通道的β亚基是增加CaV的成孔α亚基的表面表达的细胞质蛋白。我们靶向CaVα亚基内CaVβ口袋的高亲和力蛋白-蛋白界面。对接至β亚基的50，000个小分子文库的基于结构的虚拟筛选导致鉴定2-（3，5-二甲基异恶唑-4-基）-N-（（4-（（3-苯基丙基）氨基）喹唑啉-2-基）甲基）乙酰胺（IPPQ）。该小分子与CaVβ结合并抑制其与N型电压门控钙的偶联（CaV 2.2）通道，导致大鼠背根神经节感觉神经元中CaV 2.2电流的减少，体内CaV 2.2的突触前定位减少，自发兴奋性突触后电位和微小兴奋性突触后电位的频率降低，并抑制脊髓释放伤害性神经递质降钙素基因相关肽。IPPQ不靶向阿片受体，也不参与抑制性G蛋白偶联受体信号传导。IPPQ在未处理动物中具有抗伤害性，并在急性（手术后）和神经性（脊神经结扎、化疗和gp 120诱导的周围神经病变以及基因组编辑的神经病变）疼痛模型中逆转异常性疼痛和痛觉过敏。当注射到大脑中时，IPPQ不会引起运动不能或运动障碍，这是CaV2.2靶向药物的常见不良反应。IPPQ是一种喹唑啉类似物，代表了一类新型的CaV 2.2靶向化合物，可作为探针来询问CaVα-CaVβ功能，并最终开发为慢性疼痛的非阿片类治疗药物。
Inhibition of voltage-gated calcium (CaV) channels is a potential therapy for many neurological diseases including chronic pain. Neuronal CaV1/CaV2 channels are composed of α, β, γ and α2δ subunits. The β subunits of CaV channels are cytoplasmic proteins that increase the surface expression of the pore-forming α subunit of CaV. We targeted the high-affinity protein–protein interface of CaVβ’s pocket within the CaVα subunit. Structure-based virtual screening of 50,000 small molecule library docked to the β subunit led to the identification of 2-(3,5-dimethylisoxazol-4-yl)-N-((4-((3-phenylpropyl)amino)quinazolin-2-yl)methyl)acetamide (IPPQ). This small molecule bound to CaVβ and inhibited its coupling with N-type voltage-gated calcium (CaV2.2) channels, leading to a reduction in CaV2.2 currents in rat dorsal root ganglion sensory neurons, decreased presynaptic localization of CaV2.2 in vivo, decreased frequency of spontaneous excitatory postsynaptic potentials and miniature excitatory postsynaptic potentials, and inhibited release of the nociceptive neurotransmitter calcitonin gene–related peptide from spinal cord. IPPQ did not target opioid receptors nor did it engage inhibitory G protein–coupled receptor signaling. IPPQ was antinociceptive in naive animals and reversed allodynia and hyperalgesia in models of acute (postsurgical) and neuropathic (spinal nerve ligation, chemotherapy- and gp120-induced peripheral neuropathy, and genome-edited neuropathy) pain. IPPQ did not cause akinesia or motor impairment, a common adverse effect of CaV2.2 targeting drugs, when injected into the brain. IPPQ, a quinazoline analog, represents a novel class of CaV2.2-targeting compounds that may serve as probes to interrogate CaVα–CaVβ function and ultimately be developed as a nonopioid therapeutic for chronic pain.
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影响因子：
46.9
作者：
Heck, Dirk;Kowalczyk, Monika S.;Yudovich, David;Belizaire, Roger;Puram, Rishi V.;McConkey, Marie E.;Thielke, Anne;Aster, Jon C.;Regev, Aviv;Ebert, Benjamin L.
通讯作者：
Ebert, Benjamin L.
影响因子：
15
作者：
Coan, Kristin E. D.;Shoichet, Brian K.
通讯作者：
Shoichet, Brian K.
影响因子：
16.2
作者：
Bell, TJ;Thaler, C;Lipscombe, D
通讯作者：
Lipscombe, D
影响因子：
2
作者：
Cizkova, D;Marsala, J;Yaksh, TL
通讯作者：
Yaksh, TL
影响因子：
7.3
作者：
Friesner, Richard A.;Murphy, Robert B.;Mainz, Daniel T.
通讯作者：
Mainz, Daniel T.