Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 5 Yushan Road, Qingdao 266003, China.
Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266003, China.
J Med Chem. 2020 Mar 26;63(6):2974-2985. doi: 10.1021/acs.jmedchem.9b01536. Epub 2020 Mar 17.
The affinity of α-conotoxins, a class of nicotinic acetylcholine receptor (nAChR) peptide inhibitors, can be enhanced by dendrimerization. It has been hypothesized that this improvement arose from simultaneous binding of the α-conotoxins to several spatially adjacent sites. We here engineered several α-conotoxin dimers using a linker length compatible between neighboring binding sites on the same receptor. Remarkably, the dimer of α-conotoxin PeIA compared to the monomer displayed an increase in potency by 11-fold (IC = 1.9 nM) for the human α9α10 nAChR. The dimerization of α-conotoxin RgIA# resulted in a dual inhibitor that targets both α9α10 and α7 nAChR subtypes with an IC = ∼50 nM. The RgIA# dimer is therapeutically interesting because it is the first dual inhibitor that potently and selectively inhibits these two nAChR subtypes, which are both involved in the etiology of several cancers. We propose that the dimerization of α-conotoxins is a simpler and efficient alternative strategy to dendrimers for enhancing the activity of α-conotoxins.
α-芋螺毒素是一类烟碱型乙酰胆碱受体 (nAChR) 肽抑制剂，其亲和力可以通过树状聚合物（dendrimer）化得到增强。据推测，这种改善源于 α-芋螺毒素同时与几个空间相邻的位点结合。我们在这里使用与同一受体上相邻结合位点兼容的连接子长度，设计了几种 α-芋螺毒素二聚体。值得注意的是，与单体相比，α-芋螺毒素 PeIA 的二聚体对人 α9α10 nAChR 的效力增加了 11 倍（IC = 1.9 nM）。α-芋螺毒素 RgIA#的二聚化导致了一种双重抑制剂，能够靶向 α9α10 和 α7 nAChR 亚型，IC = ∼50 nM。RgIA#二聚体具有治疗意义，因为它是第一个能够有效且选择性地抑制这两种 nAChR 亚型的双重抑制剂，这两种亚型都与多种癌症的病因有关。我们提出，α-芋螺毒素的二聚化是一种比树状聚合物更简单、更有效的增强 α-芋螺毒素活性的策略。
