Osmakov Dmitry I, Khasanov Timur A, Maleeva Ekaterina E, Pavlov Vladimir M, Palikov Victor A, Belozerova Olga A, Koshelev Sergey G, Korolkova Yuliya V, Dyachenko Igor A, Kozlov Sergey A, Andreev Yaroslav A
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya 16/10, 117997 Moscow, Russia.
Moscow Center for Advanced Studies, Kulakova Str. 20, 123592 Moscow, Russia.
Toxins (Basel). 2025 Feb 21;17(3):101. doi: 10.3390/toxins17030101.
Mambalgins are peptide inhibitors of acid-sensing ion channels type 1 (ASIC1) with potent analgesic effects in models of inflammatory and neuropathic pain. To optimize recombinant peptide production and enhance pharmacological properties, we developed a mutant analog of mambalgin-1 (Mamb) through molecular modeling and site-directed mutagenesis. The resulting peptide, Mamb-AL, features methionine-to-alanine and methionine-to-leucine substitutions, allowing for a more efficient recombinant production protocol in . Electrophysiological experiments demonstrated that Mamb-AL exhibits three-fold and five-fold greater inhibition of homomeric ASIC1a and ASIC1b channels, respectively, and a two-fold increase in inhibition of heteromeric ASIC1a/3 channels compared with Mamb. In a mouse model of acetic acid-induced writhing pain, Mamb-AL showed a trend toward stronger analgesic efficacy than the wild-type peptide. These improvements in both production efficiency and pharmacological properties make Mamb-AL a valuable tool for studying ASIC channels and a promising candidate for analgesic drug development.
曼巴精是酸敏感离子通道1型（ASIC1）的肽类抑制剂，在炎症性疼痛和神经性疼痛模型中具有强效镇痛作用。为了优化重组肽的生产并增强药理特性，我们通过分子建模和定点诱变开发了曼巴精-1（Mamb）的突变类似物。所得肽Mamb-AL具有甲硫氨酸到丙氨酸以及甲硫氨酸到亮氨酸的替换，从而在大肠杆菌中实现了更高效的重组生产方案。电生理实验表明，与Mamb相比，Mamb-AL对同源ASIC1a和ASIC1b通道的抑制作用分别增强了三倍和五倍，对异源ASIC1a/3通道的抑制作用增加了两倍。在醋酸诱导的扭体疼痛小鼠模型中，Mamb-AL显示出比野生型肽更强的镇痛效果趋势。生产效率和药理特性的这些改进使Mamb-AL成为研究ASIC通道的有价值工具以及镇痛药物开发的有前景候选物。
