MQ232,一种用于治疗低钠血症和多囊肾疾病的蛇毒素衍生物。

IF 10.3 1区 医学 Q1 UROLOGY & NEPHROLOGY Journal of The American Society of Nephrology Pub Date : 2024-10-16 DOI:10.1681/ASN.0000000505
Goran Stanajic-Petrovic, Mathilde Keck, Peggy Barbe, Apolline Urman, Evelyne Correia, Pierre Isnard, Jean-Paul Duong Van Huyen, Khawla Chmeis, Sékou Siramakan Diarra, Stefano Palea, Frederic Theodoro, Anvi-Laëtitia Nguyen, Florence Castelli, Alain Pruvost, Wenchao Zhao, Christiane Mendre, Bernard Mouillac, Frank Bienaimé, Philippe Robin, Pascal Kessler, Catherine Llorens-Cortes, Denis Servent, Hervé Nozach, Bernard Maillère, Dong Guo, Charles Truillet, Nicolas Gilles
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引用次数: 0

摘要

背景:作为 V2R 拮抗剂,伐普坦于上世纪末问世。托伐普坦是治疗低钠血症和常染色体多囊肾病(ADPKD)处方最多的伐普坦。然而,由于价格问题、治疗窗口狭窄和一些副作用,它的使用并没有达到应有的广泛程度。为了发现更高效、更安全的新型 V2R 拮抗剂,我们对动物毒液进行了筛选,发现了几种有趣的多肽毒素。方法:利用人类 T 细胞检测和生物信息学来降低 MQ1 的免疫原性风险。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。对对照组大鼠进行了药效学、药代动力学、急性和慢性毒性试验。大鼠 dDAVP 诱导的低钠血症实验模型、肾囊肿体外小鼠模型和 ADPKD 小鼠同源模型用于验证 MQ232 对这些病症的疗效:在MQ1中引入了三个突变以降低其免疫原性风险。结果:在 MQ1 中引入了三个突变,以降低其免疫原性风险。MQ232的安全性体现在首毒剂量高达3,000 nmol/kg,PET成像对肾脏器官有很强的选择性,同时与肝脏几乎没有相互作用。在低钠血症模型中,MQ232的有效剂量为3 nmol/kg,随后在多囊肾模型中,MQ232显著减少了囊肿的生长:我们采用多种转化技术,尽量减少动物用量,在多个低钠血症和 ADPKD 啮齿动物模型中证明了 MQ232 的安全性和有效性。
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A Snake Toxin Derivative for Treatment of Hyponatremia and Polycystic Kidney Diseases.
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来源期刊
Journal of The American Society of Nephrology
Journal of The American Society of Nephrology 医学-泌尿学与肾脏学
CiteScore
22.40
自引率
2.90%
发文量
492
审稿时长
3-8 weeks
期刊介绍: The Journal of the American Society of Nephrology (JASN) stands as the preeminent kidney journal globally, offering an exceptional synthesis of cutting-edge basic research, clinical epidemiology, meta-analysis, and relevant editorial content. Representing a comprehensive resource, JASN encompasses clinical research, editorials distilling key findings, perspectives, and timely reviews. Editorials are skillfully crafted to elucidate the essential insights of the parent article, while JASN actively encourages the submission of Letters to the Editor discussing recently published articles. The reviews featured in JASN are consistently erudite and comprehensive, providing thorough coverage of respective fields. Since its inception in July 1990, JASN has been a monthly publication. JASN publishes original research reports and editorial content across a spectrum of basic and clinical science relevant to the broad discipline of nephrology. Topics covered include renal cell biology, developmental biology of the kidney, genetics of kidney disease, cell and transport physiology, hemodynamics and vascular regulation, mechanisms of blood pressure regulation, renal immunology, kidney pathology, pathophysiology of kidney diseases, nephrolithiasis, clinical nephrology (including dialysis and transplantation), and hypertension. Furthermore, articles addressing healthcare policy and care delivery issues relevant to nephrology are warmly welcomed.
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