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 (K_i = 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.

中文翻译：

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加压素 V2 受体的长滞留时间肽拮抗剂治疗常染色体显性多囊肾病

肾脏中细胞内 cAMP 失调会驱动常染色体显性多囊肾病 (ADPKD) 的囊肿发生和进展。越来越多的证据支持加压素 V ₂受体 (V ₂ R) 拮抗作用可有效降低 cAMP 水平，从而验证了该受体作为治疗靶点的有效性。托伐普坦是 FDA 批准的 V ₂ R 拮抗剂，其治疗 ADPKD 的临床疗效显示出局限性。因此，寻找同类中更好、疗效更佳的V ₂ R 拮抗剂仍然刻不容缓。在此，我们合成了一组肽V ₂ R拮抗剂。肽33对 V ₂ R ( K _i = 6.1 ± 1.5 nM)表现出高结合亲和力，并且停留时间延长至 20 ± 1 分钟，是托伐普坦的 2 倍。在冲洗实验中，这种长时间的相互作用转化为对 cAMP 产生的持续抑制。此外，在 ADPKD 的离体和体内模型中，肽33均表现出优于托伐普坦的功效，强调了其作为治疗 ADPKD 的有前途的先导化合物的潜力。