Abstract：
The dysregulated intracellular cAMP in the kidneys drives cystogenesis and progression in autosomal dominant polycystic kidney disease (ADPKD). Mounting evidence supports that vasopressin V2 receptor (V2R) antagonism effectively reduces cAMP levels, validating this receptor as a therapeutic target. Tolvaptan, an FDA-approved V2R antagonist, shows limitations in its clinical efficacy for ADPKD treatment. Therefore, the pursuit of better-in-class V2R antagonists with an improved efficacy remains pressing. Herein, we synthesized a set of peptide V2R antagonists. Peptide 33 exhibited a high binding affinity for the V2R (Ki = 6.1 ± 1.5 nM) and an extended residence time of 20 ± 1 min, 2-fold that of tolvaptan. This prolonged interaction translated into sustained suppression of cAMP production in washout experiments. Furthermore, peptide 33 exhibited improved efficacies over tolvaptan in both ex vivo and in vivo models of ADPKD, underscoring its potential as a promising lead compound for the treatment of ADPKD.
摘要：
肾脏中细胞内cAMP失调驱动常染色体显性多囊肾病(ADPKD)的膀胱形成和进展。越来越多的证据支持加压素V2受体（V2R）拮抗作用有效降低cAMP水平，验证该受体作为治疗靶标。托伐普坦,FDA批准的V2R拮抗剂，在ADPKD治疗的临床疗效方面显示出局限性。因此,寻求具有改善疗效的同类更好的V2R拮抗剂仍然紧迫。在这里，我们合成了一组肽V2R拮抗剂。肽33表现出对V2R的高结合亲和力(Ki=6.1±1.5nM)和20±1分钟的延长停留时间。是托伐普坦的2倍。在冲洗实验中，这种延长的相互作用转化为持续抑制cAMP产生。此外，肽33在ADPKD的离体和体内模型中显示出比托伐普坦改善的功效，强调其作为治疗ADPKD的有希望的先导化合物的潜力。
