Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, United States.
J Med Chem. 2021 Jun 24;64(12):8384-8390. doi: 10.1021/acs.jmedchem.1c00380. Epub 2021 May 12.
High susceptibility to proteolytic degradation in the gastrointestinal tract limits the therapeutic application of peptide drugs in gastrointestinal disorders. Linaclotide is an orally administered peptide drug for the treatment of irritable bowel syndrome with constipation (IBS-C) and abdominal pain. Linaclotide is however degraded in the intestinal environment within 1 h, and improvements in gastrointestinal stability might enhance its therapeutic application. We therefore designed and synthesized a series of linaclotide analogues employing a variety of strategic modifications and evaluated their gastrointestinal stability and pharmacological activity at its target receptor guanylate cyclase-C. All analogues had substantial improvements in gastrointestinal half-lives (>8 h vs linaclotide 48 min), and most remained active at low nanomolar concentrations. This work highlights strategic approaches for the development of gut-stable peptides toward the next generation of orally administered peptide drugs for the treatment of gastrointestinal disorders.
在胃肠道中高度易被蛋白水解降解，限制了肽类药物在胃肠道疾病中的治疗应用。利那洛肽是一种口服肽类药物，用于治疗便秘型肠易激综合征（IBS-C）和腹痛。然而，利那洛肽在肠道环境中 1 小时内被降解，改善胃肠道稳定性可能会增强其治疗应用。因此，我们设计并合成了一系列利那洛肽类似物，采用了多种策略修饰，并评估了它们在其靶受体鸟苷酸环化酶（GC-C）上的胃肠道稳定性和药理活性。所有类似物的胃肠道半衰期均有显著提高（>8 h 比利那洛肽 48 min），并且大多数在低纳摩尔浓度下仍保持活性。这项工作强调了开发胃肠道稳定肽的策略方法，以开发下一代用于治疗胃肠道疾病的口服肽类药物。
