Département de Pharmacologie-Physiologie, Institut de Pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e av nord, Sherbrooke, Quebec, Canada J1H5N4.
Department of Chemistry and Applied Biosciences, ETH Zürich, Vladimir-Prelog-Weg 2, 8093 Zürich, Switzerland.
J Med Chem. 2021 May 13;64(9):5365-5383. doi: 10.1021/acs.jmedchem.0c02036. Epub 2021 Mar 22.
Incorporating small modifications to peptidic macrocycles can have a major influence on their properties. For instance, N-methylation has been shown to impact permeability. A better understanding of the relationship between permeability and structure is of key importance as peptidic drugs are often associated with unfavorable pharmacokinetic profiles. Starting from a semipeptidic macrocycle backbone composed of a tripeptide tethered head-to-tail with an alkyl linker, we investigated two small changes: peptide-to-peptoid substitution and various methyl placements on the nonpeptidic linker. Implementing these changes in parallel, we created a collection of 36 compounds. Their permeability was then assessed in parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays. Our results show a systematic improvement in permeability associated with one peptoid position in the cycle, while the influence of methyl substitution varies on a case-by-case basis. Using a combination of molecular dynamics simulations and NMR measurements, we offer hypotheses to explain such behavior.
对缩肽大环进行微小的修饰可以对其性质产生重大影响。例如，N-甲基化已被证明会影响通透性。更好地理解通透性和结构之间的关系非常重要，因为肽类药物通常与不利的药代动力学特征相关。我们从一个由三肽通过烷基键头到尾连接而成的半缩肽大环骨架开始，研究了两个小的变化：肽到肽键的取代以及非肽连接子上的各种甲基取代。我们平行地实施这些变化，创建了一个包含 36 种化合物的集合。然后在平行人工膜渗透测定（PAMPA）和 Caco-2 测定中评估它们的通透性。我们的结果表明，与环中的一个肽键位置相关的通透性得到了系统的改善，而甲基取代的影响则因情况而异。我们使用分子动力学模拟和 NMR 测量相结合的方法，提出了一些假设来解释这种行为。
