Seisel Quentin, Lakumpa Israpong, Josse Emilie, Vivès Eric, Varilh Jessica, Taulan-Cadars Magali, Boisguérin Prisca
CRBM, University of Montpellier, CNRS UMR 5237, 34000 Montpellier, France.
PhyMedExp, Bâtiment Crastes de Paulet, University of Montpellier, INSERM U1046, CNRS UMR 9214, 34000 Montpellier, France.
Pharmaceutics. 2022 Apr 7;14(4):808. doi: 10.3390/pharmaceutics14040808.
Therapeutic peptides have regained interest as they can address unmet medical needs and can be an excellent complement to pharmaceutic small molecules and other macromolecular therapeutics. Over the past decades, correctors and potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride ion channel causing cystic fibrosis (CF) when mutated, were developed to reduce the symptoms of the patients. In this context, we have previously designed a CFTR-stabilizing iCAL36 peptide able to further increase the CFTR amount in epithelial cells, thereby resulting in a higher CFTR activity. In the present study, optimization of the peptidyl inhibitor was performed by coupling five different cell-penetrating peptides (CPP), which are Tat, dTat, TatRI (), MPG, and Penetratin. Screening of the internalization properties of these CPP-iCAL36 peptides under different conditions (with or without serum or endocytosis inhibitors, etc.) was performed to select TatRI as the optimal CPP for iCAL36 delivery. More importantly, using this TatRI-iCAL36 peptide, we were able to reveal for the first time an additive increase in the CFTR amount in the presence of VX-445/VX-809 compared to VX-445/VX-809 treatment alone. This finding is a significant contribution to the development of CFTR-stabilizing peptides in addition to currently used treatments (small-molecule correctors or potentiators) for CF patients.
治疗性肽重新引起了人们的关注，因为它们可以满足未被满足的医疗需求，并且可以成为药物小分子和其他大分子疗法的极佳补充。在过去几十年中，开发了囊性纤维化跨膜传导调节因子（CFTR）的校正剂和增强剂，CFTR是一种氯离子通道，发生突变时会导致囊性纤维化（CF），这些校正剂和增强剂用于减轻患者症状。在此背景下，我们之前设计了一种CFTR稳定肽iCAL36，它能够进一步增加上皮细胞中的CFTR量，从而导致更高的CFTR活性。在本研究中，通过偶联五种不同的细胞穿透肽（CPP），即Tat、dTat、TatRI（）、MPG和穿膜肽，对肽基抑制剂进行了优化。在不同条件下（有或无血清或内吞作用抑制剂等）对这些CPP-iCAL36肽的内化特性进行筛选，以选择TatRI作为iCAL36递送的最佳CPP。更重要的是，使用这种TatRI-iCAL36肽，我们首次发现，与单独使用VX-445/VX-809治疗相比，在VX-445/VX-809存在的情况下，CFTR量会有累加性增加。这一发现除了目前用于CF患者的治疗方法（小分子校正剂或增强剂）之外，对CFTR稳定肽的开发做出了重大贡献。
