二价 NaV 毒素的效力和亚型选择性的变化是结特异性的,Bioconjugate Chemistry

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二价 NaV 毒素的效力和亚型选择性的变化是结特异性的
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2023-06-01 , DOI: 10.1021/acs.bioconjchem.3c00135
Poanna Tran ₁ , Hue N T Tran ₁ , Kirsten L McMahon ₁ , Jennifer R Deuis ₁ , Lotten Ragnarsson ₁ , Alexander Norman _{2,

3} , Simon J Sharpe ₄ , Richard J Payne _{2,

3} , Irina Vetter _{1,

5} , Christina I Schroeder _{1,

6,

7}

Affiliation

长期以来，人们一直在研究富含二硫键的肽毒素，因为它们具有抑制电压门控钠通道亚型 Na _V 1.7 的能力，而 Na V 1.7 是治疗疼痛的有效靶点。在本研究中，我们试图将芋螺毒素的孔阻塞活性与蜘蛛毒素的门控修饰剂活性结合起来，设计出具有更高效力和选择性的新型 Na _V 1.7 二价抑制剂。为此，我们创建了一系列异二聚体毒素，旨在针对人类 Na _V1.7 通过将芋螺毒素与蜘蛛毒素连接并评估所得二价毒素的效力和选择性。为此，使用了一系列蜘蛛衍生的门控修饰毒素（GpTx-1、ProTx-II、gHwTx-IV、JzTx-V、CcoTx-1 和 Pn3a）和两种毛孔阻断剂 μ-芋螺毒素 SxIIIC 和 KIIIA学习。我们采用分选酶 A 进行酶促连接以进行 C 至 N 末端连接，或采用点击化学进行 N 至 N 末端连接。_{ProTx-II 和 SxIIIC (Pro[LPATG 6} ]Sx)连接产生的二价肽被证明是最佳组合，因为连接后 hNa _V 1.7 的天然 ProTx-II 效力得以保留。At hNa _V1.4，观察到孔阻断剂和门控修饰剂毒素部分之间的协同效应，导致与母体肽相比钠通道亚型选择性改变。包括突变二价肽和突变 hNa _V 1.7 通道在内的进一步研究表明，门控修饰毒素对二价肽的效力比孔阻滞剂有更大的贡献。_{这项研究描述了设计针对 hNa V} 1.7的药理学混合肽的潜在优点和缺点。

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Changes in Potency and Subtype Selectivity of Bivalent NaV Toxins are Knot-Specific

Disulfide-rich peptide toxins have long been studied for their ability to inhibit voltage-gated sodium channel subtype Na_V1.7, a validated target for the treatment of pain. In this study, we sought to combine the pore blocking activity of conotoxins with the gating modifier activity of spider toxins to design new bivalent inhibitors of Na_V1.7 with improved potency and selectivity. To do this, we created an array of heterodimeric toxins designed to target human Na_V1.7 by ligating a conotoxin to a spider toxin and assessed the potency and selectivity of the resulting bivalent toxins. A series of spider-derived gating modifier toxins (GpTx-1, ProTx-II, gHwTx-IV, JzTx-V, CcoTx-1, and Pn3a) and two pore-blocker μ-conotoxins, SxIIIC and KIIIA, were used for this study. We employed either enzymatic ligation with sortase A for C- to N-terminal ligation or click chemistry for N- to N-terminal ligation. The bivalent peptide resulting from ligation of ProTx-II and SxIIIC (Pro[LPATG₆]Sx) was shown to be the best combination as native ProTx-II potency at hNa_V1.7 was conserved following ligation. At hNa_V1.4, a synergistic effect between the pore blocker and gating modifier toxin moieties was observed, resulting in altered sodium channel subtype selectivity compared to the parent peptides. Further studies including mutant bivalent peptides and mutant hNa_V1.7 channels suggested that gating modifier toxins have a greater contribution to the potency of the bivalent peptides than pore blockers. This study delineated potential benefits and drawbacks of designing pharmacological hybrid peptides targeting hNa_V1.7.

更新日期：2023-06-01

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