Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Bioorg Med Chem. 2018 Mar 15;26(6):1203-1205. doi: 10.1016/j.bmc.2017.10.037. Epub 2017 Oct 31.
Peptides are promising scaffolds for use as therapeutics, targeting interactions previously considered to be "undruggable" by small molecules. While short peptides are generally unstructured in solution and rapidly degraded by proteases in the cell cytosol, peptide stapling offers an effective method to both stabilize peptides in a helical structure and increase resistance to proteolytic degradation. Most studies of peptide stapling have focused on residues with i, i + 4 and i, i + 7 spacing, while stapling of residues with i, i + 3 spacing has been understudied. Herein, we evaluated a suite of bifunctional linkers for stapling between residues with i, i + 3 spacing, comparing the ability of each compound to react with the peptide and the degree of helicity conferred. Finally, we evaluated the ability of the stapling to increase proteolytic resistance in cell lysates, comparing stapling of i, i + 3 and i, i + 4 spacing, with i, i + 3 spacing resulting in a greater increase in peptide half-life in the model system. This presents an effective stapling strategy, adding to the peptide stapling toolbox.
肽是一种很有前途的治疗药物支架，可针对小分子药物以前认为“不可成药”的相互作用。虽然短肽在溶液中通常无定形且在细胞质溶胶中迅速被蛋白酶降解，但肽键合提供了一种有效方法，可使肽稳定在螺旋结构中并增加对蛋白水解降解的抗性。肽键合的大多数研究都集中在 i、i+4 和 i、i+7 间距的残基上，而 i、i+3 间距残基的键合研究较少。在此，我们评估了一系列用于 i、i+3 间距残基键合的双功能接头，比较了每种化合物与肽反应的能力和赋予的螺旋程度。最后，我们评估了键合在细胞裂解物中增加蛋白水解抗性的能力，比较了 i、i+3 和 i、i+4 间距的键合，i、i+3 间距的键合使模型系统中肽半衰期的增加更大。这提出了一种有效的键合策略，为肽键合工具增添了新的内容。
