Journal of the American Society of Nephrology : JASN · 2024
A Snake Toxin Derivative for Treatment of Hyponatremia and Polycystic Kidney Diseases.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Stanajic-Petrovic Goran, Keck Mathilde, Barbe Peggy, Urman Apolline, Correia Evelyne, Isnard Pierre, Duong Van Huyen Jean-Paul, Chmeis Khawla, Diarra Sékou Siramakan, Palea Stefano, Theodoro Frederic, Nguyen Anvi-Laëtitia, Castelli Florence, Pruvost Alain, Zhao Wenchao, Mendre Christiane, Mouillac Bernard, Bienaimé Frank, Robin Philippe, Kessler Pascal, Llorens-Cortes Catherine, Servent Denis, Nozach Hervé, Maillère Bernard, Guo Dong, Truillet Charles, Gilles Nicolas
Аннотация
KEY POINTS: MQ232, a disulfide-bond reticulated peptide derived from a natural snake toxin, was optimized as a new aquaretic drug candidate. MQ232 showed very low acute and chronic toxicity in rat and a biodistribution in mice strongly in favor of the kidney organs. MQ232 induced a sole aquaretic effect and demonstrated high in vivo activities on hyponatremia and polycystic kidney disease models.
BACKGROUND: Vaptans were developed at the end of the previous century as vasopressin type 2 receptor antagonists. Tolvaptan is the most prescribed vaptan for hyponatremia and autosomal dominant 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 vasopressin type 2 receptor antagonists, we screened animal venoms and identified several peptide toxins. Among them, mambaquaretin 1 (MQ1) displayed 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 were used to mitigate MQ1 immunogenicity risk. MQ232 biodistribution in mice was performed by positron emission tomography. Pharmacodynamics, pharmacokinetics, and acute and chronic toxicity tests were performed on control rats. A rat experimental model of desmopressin-induced hyponatremia, ex vivo mice model of kidney cysts, and 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 3000 nmol/kg and a strong kidney organ selectivity by positron emission tomography 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, using diverse translational techniques and minimizing animal use, MQ232's safety and efficacy in several rodent models of hyponatremia and ADPKD.
BACKGROUND: Vaptans were developed at the end of the previous century as vasopressin type 2 receptor antagonists. Tolvaptan is the most prescribed vaptan for hyponatremia and autosomal dominant 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 vasopressin type 2 receptor antagonists, we screened animal venoms and identified several peptide toxins. Among them, mambaquaretin 1 (MQ1) displayed 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 were used to mitigate MQ1 immunogenicity risk. MQ232 biodistribution in mice was performed by positron emission tomography. Pharmacodynamics, pharmacokinetics, and acute and chronic toxicity tests were performed on control rats. A rat experimental model of desmopressin-induced hyponatremia, ex vivo mice model of kidney cysts, and 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 3000 nmol/kg and a strong kidney organ selectivity by positron emission tomography 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, using diverse translational techniques and minimizing animal use, MQ232's safety and efficacy in several rodent models of hyponatremia and ADPKD.