Department of Chemical, Materials and Production Engineering (DICMaPI), University of Naples Federico II, 80125 Naples, Italy.
Interdisciplinary Research Center on Biomaterials, CRIB, University of Naples Federico II, 80125 Naples, Italy.
Molecules. 2022 Oct 8;27(19):6696. doi: 10.3390/molecules27196696.
The family of synthetic peptide angiopeps, and particularly angiopep-2 (ANG-2) demonstrated the ability preclinically and clinically to shuttle active molecules across the blood-brain barrier (BBB) and selectively toward brain tumor cells. The literature has also proved that the transport occurs through a specific receptor-mediated transcytosis of the peptide by LRP-1 receptors present both on BBB and tumor cell membranes. However, contradictory results about exploiting this promising mechanism to engineer complex delivery systems, such as nanoparticles, are being obtained.
For this reason, we applied a molecular docking (MD)-based strategy to investigate the molecular interaction of ANG-2 and the LRP-1 ligand-binding moieties (CR56 and CR17), clarifying the impact of peptide conjugation on its transport mechanism.
MD results proved that ANG-2/LRP-1 binding involves the majority of ANG-2 residues, is characterized by high binding energies, and that it is site-specific for CR56 where the binding to 929ASP recalls a transcytosis mechanism, resembling the binding of the receptor to the receptor-associated protein. On the other hand, ANG-2 binding to CR17 is less site-specific but, as proved for apolipoprotein internalization in physiological conditions, it involves the ANG-2 lysin residue.
Overall, our results proved that ANG-2 energetic interaction with the LRP-1 receptor is not hindered if specific residues of the peptide are chemically crosslinked to simple or complex engineered delivery systems.
合成肽血管肽家族，特别是血管肽-2（ANG-2），在临床前和临床研究中表现出穿过血脑屏障（BBB）并选择性地向脑肿瘤细胞输送活性分子的能力。文献还证明，这种转运是通过存在于 BBB 和肿瘤细胞膜上的 LRP-1 受体的特定受体介导的肽胞吞作用发生的。然而，关于利用这一有前途的机制来设计复杂的递药系统（如纳米颗粒）的结果却存在矛盾。
为此，我们应用基于分子对接（MD）的策略来研究 ANG-2 与 LRP-1 配体结合结构域（CR56 和 CR17）的分子相互作用，阐明肽结合对其转运机制的影响。
MD 结果证明，ANG-2/LRP-1 结合涉及 ANG-2 的大部分残基，具有高结合能，并且是特异性结合 CR56 的，其中与 929ASP 的结合类似于受体与受体相关蛋白的结合，提示了一种转胞吞作用机制。另一方面，ANG-2 与 CR17 的结合不太具有特异性，但正如在生理条件下内吞载脂蛋白所证明的那样，它涉及 ANG-2 的赖氨酸残基。
总的来说，我们的结果证明，如果肽的特定残基被化学交联到简单或复杂的工程递药系统上，ANG-2 与 LRP-1 受体的能量相互作用不会受到阻碍。
