Akondi K B, Lewis R J, Alewood P F
Institute for Molecular Bioscience (IMB), The University of Queensland, Brisbane, 4072, Queensland, Australia.
Biopolymers. 2014 Apr;101(4):347-54. doi: 10.1002/bip.22368.
Voltage-gated sodium (Nav) channels are responsible for generation and propagation of action potentials throughout the nervous system. Their malfunction causes several disorders and chronic conditions including neuropathic pain. Potent subtype specific ligands are essential for deciphering the molecular mechanisms of Nav channel function and development of effective therapeutics. µ-Conotoxin SIIIA is a potent mammalian Nav 1.2 channel blocker that exhibits analgesic activity in rodents. We undertook to reengineer loop 1 through a strategy involving charge alterations and truncations which led to the development of µ-SIIIA mimetics with novel selectivity profiles. A novel [N5K/D15A]SIIIA(3-20) mutant with enhanced net positive charge showed a dramatic increase in its Nav 1.2 potency (IC50 of 0.5 nM vs. 9.6 nM for native SIIIA) though further truncations led to loss of potency. Unexpectedly, it appears that SIIIA loop 1 significantly influences its Nav channel interactions despite loop 2 and 3 residues constituting the pharmacophore. This minimal functional conotoxin scaffold may allow further development of selective NaV blockers.
电压门控钠（Nav）通道负责在整个神经系统中产生和传播动作电位。其功能异常会导致多种疾病和慢性病症，包括神经性疼痛。强效的亚型特异性配体对于解读Nav通道功能的分子机制以及开发有效的治疗方法至关重要。μ-芋螺毒素SIIIA是一种强效的哺乳动物Nav 1.2通道阻滞剂，在啮齿动物中表现出镇痛活性。我们通过一种涉及电荷改变和截短的策略对环1进行重新设计，从而开发出具有新型选择性谱的μ-SIIIA模拟物。一种净正电荷增强的新型[N5K/D15A]SIIIA(3 - 20)突变体，其对Nav 1.2的效力显著增加（IC50为0.5 nM，而天然SIIIA为9.6 nM），不过进一步截短会导致效力丧失。出乎意料的是，尽管环2和环3残基构成药效团，但SIIIA环1似乎对其与Nav通道的相互作用有显著影响。这种最小功能的芋螺毒素支架可能有助于选择性NaV阻滞剂的进一步开发。
