Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
J Am Chem Soc. 2017 Nov 8;139(44):15628-15631. doi: 10.1021/jacs.7b09790. Epub 2017 Oct 30.
Here we describe the utility of peptide macrocyclization through perfluoroaryl-cysteine SAr chemistry to improve the ability of peptides to cross the blood-brain barrier. Multiple macrocyclic analogues of the peptide transportan-10 were investigated that displayed increased uptake in two different cell lines and improved proteolytic stability. One of these analogues (M13) exhibited substantially increased delivery across a cellular spheroid model of the blood-brain barrier. Through ex vivo imaging of mouse brains, we demonstrated that this perfluoroarene-based macrocycle of TP10 exhibits increased penetration of the brain parenchyma following intravenous administration in mice. Finally, we evaluated macrocyclic analogues of the BH3 domain of the BIM protein to assess if our approach would be applicable to a peptide of therapeutic interest. We identified a BIM BH3 analogue that showed increased penetration of the brain tissue in mice.
在这里，我们描述了通过全氟芳基-半胱氨酸 SAr 化学进行肽大环化来提高肽穿过血脑屏障能力的用途。研究了多种穿膜肽转运蛋白-10 的大环类似物，这些类似物在两种不同的细胞系中显示出增加的摄取，并提高了蛋白水解稳定性。其中一种类似物（M13）在血脑屏障的细胞球体模型中显示出显著增加的递药作用。通过对小鼠大脑的离体成像，我们证明了这种基于全氟芳烃的 TP10 大环化合物在小鼠静脉给药后能够增加对脑实质的穿透。最后，我们评估了 BIM 蛋白 BH3 结构域的大环类似物，以评估我们的方法是否适用于具有治疗意义的肽。我们鉴定了一种 BIM BH3 类似物，它在小鼠中显示出增加的脑组织穿透性。
