寡精氨酸肽：一种新型烟碱型乙酰胆碱受体抑制剂。
Oligoarginine Peptides, a New Family of Nicotinic Acetylcholine Receptor Inhibitors.
机构信息
Department of Molecular Neuroimmune Signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia (D.S.L., E.V.K., I.A.I., N.S.E., N.D.T., E.N.S., E.Y.T., A.E.S., D.S.K., I.E.K., V.I.T.); Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., S.J.T.); Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia (I.E.K.); Institute of Chemistry and Molecular Engineering, Agricultural University of Georgia, Kakha Bendukidze University Campus, Tbilisi, Georgia (R.K., N.Z., I.I.); and PhysBio of MePhI, Moscow, Russia (V.I.T.).
Department of Molecular Neuroimmune Signaling, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia (D.S.L., E.V.K., I.A.I., N.S.E., N.D.T., E.N.S., E.Y.T., A.E.S., D.S.K., I.E.K., V.I.T.); Department of Neurobiology, Hellenic Pasteur Institute, Athens, Greece (M.Z., S.J.T.); Institute of Molecular Medicine, Sechenov First Moscow State Medical University, Moscow, Russia (I.E.K.); Institute of Chemistry and Molecular Engineering, Agricultural University of Georgia, Kakha Bendukidze University Campus, Tbilisi, Georgia (R.K., N.Z., I.I.); and PhysBio of MePhI, Moscow, Russia (V.I.T.)
出版信息
Mol Pharmacol. 2019 Nov;96(5):664-673. doi: 10.1124/mol.119.117713. Epub 2019 Sep 6.
Many peptide ligands of nicotinic acetylcholine receptors (nAChRs) contain a large number of positively charged amino acid residues, a striking example being conotoxins RgIA and GeXIVA from marine mollusk venom, with an arginine content of >30%. To determine whether peptides built exclusively from arginine residues will interact with different nAChR subtypes or with their structural homologs such as the acetylcholine-binding protein and ligand-binding domain of the nAChR 9 subunit, we synthesized a series of R3, R6, R8, and R16 oligoarginines and investigated their activity by competition with radioiodinated -bungarotoxin, two-electrode voltage-clamp electrophysiology, and calcium imaging. R6 and longer peptides inhibited muscle-type nAChRs, 7 nAChRs, and 32 nAChRs in the micromolar range. The most efficient inhibition of ion currents was detected for muscle nAChR by R16 (IC = 157 nM) and for the 910 subtype by R8 and R16 (IC = 44 and 120 nM, respectively). Since the R8 affinity for other tested nAChRs was 100-fold lower, R8 appears to be a selective antagonist of 910 nAChR. For R8, the electrophysiological and competition experiments indicated the existence of two distinct binding sites on 910 nAChR. Since modified oligoarginines and other cationic molecules are widely used as cell-penetrating peptides, we studied several cationic polymers and demonstrated their nAChR inhibitory activity. SIGNIFICANT STATEMENT: By using radioligand analysis, electrophysiology, and calcium imaging, we found that oligoarginine peptides are a new group of inhibitors for muscle nicotinic acetylcholine receptors (nAChRs) and some neuronal nAChRs, the most active being those with 16 and 8 Arg residues. Such compounds and other cationic polymers are cell-penetrating tools for drug delivery, and we also demonstrated the inhibition of nAChRs for several of the latter. Possible positive and negative consequences of such an action should be taken into account.
许多烟碱型乙酰胆碱受体（nAChRs）的肽配体含有大量带正电荷的氨基酸残基，一个显著的例子是来自海洋软体动物毒液的 RgIA 和 GeXIVA 短肽，其精氨酸含量超过 30%。为了确定仅由精氨酸残基组成的肽是否会与不同的 nAChR 亚型相互作用，或者与它们的结构同源物（如乙酰胆碱结合蛋白和 nAChR 9 亚基的配体结合域）相互作用，我们合成了一系列 R3、R6、R8 和 R16 寡聚精氨酸，并通过放射性碘标记的 -bungarotoxin 竞争、双电极电压钳电生理学和钙成像来研究它们的活性。R6 和更长的肽以微摩尔范围抑制肌肉型 nAChR、7 nAChR 和 32 nAChR。R16 对肌肉 nAChR 的离子电流抑制作用最为有效（IC = 157 nM），R8 和 R16 对 910 亚型的抑制作用（IC = 44 和 120 nM）。由于 R8 对其他测试的 nAChR 的亲和力低 100 倍，因此 R8 似乎是 910 nAChR 的选择性拮抗剂。对于 R8，电生理学和竞争实验表明在 910 nAChR 上存在两个不同的结合位点。由于修饰的寡聚精氨酸和其他阳离子分子被广泛用作穿透细胞的肽，我们研究了几种阳离子聚合物并证明了它们对 nAChR 的抑制活性。重要说明：通过使用放射性配体分析、电生理学和钙成像，我们发现寡聚精氨酸肽是一组新的肌肉烟碱型乙酰胆碱受体（nAChR）和一些神经元 nAChR 的抑制剂，其中最活跃的是具有 16 和 8 个精氨酸残基的肽。此类化合物和其他阳离子聚合物是用于药物递送的穿透细胞工具，我们还证明了其中几种对 nAChR 的抑制作用。应该考虑到这种作用的可能积极和消极后果。
Zotero 插件