BACKGROUND Vaptans were developed at the end of the previous century as V2R antagonists. Tolvaptan is the most prescribed vaptan for hyponatremia and the autosomal polycystic kidney disease (ADPKD). However, its use is not as widespread as it should be due to price issues, a narrow therapeutic window and some side effects. With the aim of discovering new efficient and safer V2R antagonists, we screened animal venoms and identified several interesting peptide toxins. Among them, MQ1 displayed such unique biological properties in that regard that it was the starting point for the development of a potential drug candidate. METHODS Human T-cell assays and bioinformatics was used to mitigate MQ1 immunogenicity risk. The MQ232 biodistribution in mice was done by positron emission tomography (PET). Pharmacodynamics, pharmacokinetics, acute and chronic toxicity tests were performed on control rats. A rat experimental model of dDAVP-induced hyponatremia, an ex vivo mice model of renal cysts and a mice orthologous model of ADPKD were used to validate MQ232 efficacy in these pathologies. RESULTS Three mutations were introduced in MQ1 to mitigate its immunogenicity risk. A fourth gain-of-function mutation was added to generate MQ232. MQ232's safety was demonstrated by a first toxic dose as high as 3,000 nmol/kg and a strong kidney organ selectivity by PET imaging, while showing almost no interaction with the liver. MQ232's efficacy was first demonstrated with an effective dose of 3 nmol/kg in a hyponatremic model, and then in polycystic kidney models on which MQ232 significantly reduced cyst growth. CONCLUSIONS We demonstrated, employing diverse translational techniques and minimizing animal use, MQ232's safety and efficacy in several rodent models of hyponatremia and ADPKD.

中文翻译：

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一种用于治疗低钠血症和多囊肾病的蛇毒素衍生物。


背景 Vaptans 是在上世纪末作为 V2R 拮抗剂开发的。托伐普坦是治疗低钠血症和常染色体多囊肾病 （ADPKD） 的最常用处方 vaptan。然而，由于价格问题、狭窄的治疗窗口和一些副作用，它的使用并不像应有的那样广泛。为了发现新的高效且更安全的 V2R 拮抗剂，我们筛选了动物毒液并鉴定了几种有趣的肽毒素。其中，MQ1 在这方面表现出如此独特的生物学特性，使其成为开发潜在候选药物的起点。方法 采用人 T 细胞检测和生物信息学降低 MQ1 免疫原性风险。MQ232 在小鼠体内的生物分布是通过正电子发射断层扫描 （PET） 完成的。对对照大鼠进行药效学、药代动力学、急性和慢性毒性试验。使用 dDAVP 诱导的低钠血症大鼠实验模型、肾囊肿离体小鼠模型和 ADPKD 小鼠直系同源模型来验证 MQ232 在这些病理中的疗效。结果 MQ1 中引入了 3 个突变以降低其免疫原性风险。添加了第四个功能获得性突变以产生 MQ232。MQ232 的安全性通过高达 3,000 nmol/kg 的首次毒性剂量和 PET 成像的强肾器官选择性证明，同时显示与肝脏几乎没有相互作用。MQ232 的疗效首先在低钠血症模型中以 3 nmol/kg 的有效剂量得到证明，然后在多囊肾模型中得到证明，MQ232 显着减少了囊肿生长。结论 我们采用多种转化技术并尽量减少动物使用，证明了 MQ232 在几种低钠血症和 ADPKD 啮齿动物模型中的安全性和有效性。