Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.
Institute of Physical Chemistry, Polish Academy of Sciences, Warsaw, Poland.
J Mol Recognit. 2020 Jan;33(1):e2811. doi: 10.1002/jmr.2811. Epub 2019 Sep 9.
Amyloid fibrils are rigid β-pleated protein aggregates that are connected with series of harmful diseases and at the same time are promising as base for novel nanomaterials. Thus, design of compounds able to inhibit or redirect those aggregates formation is important both for the biomedical aims and for nanotechnology applications. Here, we studied the effect of tetraphenylporphyrins (metal free, their Cu and Pd complexes, and those functionalized by carboxy and amino groups on periphery) on insulin amyloid self-assembling. The strongest impact on insulin aggregation was demonstrated by a metal-free porphyrin bearing four carboxy groups. This compound strongly suppresses insulin aggregation (about 88% reduction in amyloid-sensitive probe emission) inducing formation of fibrils with the length close to this of free insulin (1.7 ± 0.6 μm as compared with 1.4 ± 0.4 μm, respectively) with an essentially reduced tendency to lateral aggregation. Contrarily, the presence of tetraphenylporphyrin containing four amino groups only slightly affects fibrils' morphology and makes weaker impact on insulin aggregation yield (about 44% reduction). This is explained by the ability of aromatic carboxy groups of 5,10,15,20-(tetra-4-carboxyphenyl)porphyrin to interact with complementary protein-binding groups and thus stabilize the supramolecular complex. For 5,10,15,20-(tetra-4-aminophenyl)porphyrin, full protonation takes place in acidic medium of protein aggregation reaction; this results in the high positive charge of TPPN4 (equal or close to +6) and hence higher contribution of coulombic repulsion to interaction of TPPN4 with insulin. One more possible mechanism of the lower inhibition effect of TPPN4 as compared with TPPC4 could be the more restricted possibility of the former as compared with the latter to form H bonds with insulin groups. It was also shown that metal-free, Pd-containing, and Cu-containing tetraphenylporphyrins without peripheral substituents make almost the same impact on the protein self-assembling. We suppose this to be due to coordination saturation of these metal atoms.
淀粉样纤维是刚性的β-折叠蛋白聚集体，与一系列有害疾病有关，同时也有望成为新型纳米材料的基础。因此，设计能够抑制或改变这些聚集体形成的化合物对于生物医学和纳米技术应用都很重要。在这里，我们研究了四苯基卟啉（无金属、其 Cu 和 Pd 配合物以及外围羧基和氨基官能化的配合物）对胰岛素淀粉样自组装的影响。具有四个羧基的无金属卟啉对胰岛素聚集的影响最强。该化合物强烈抑制胰岛素聚集（约 88%降低淀粉样敏感探针发射），诱导形成与游离胰岛素长度相近的纤维（分别为 1.7±0.6μm 和 1.4±0.4μm），侧向聚集的趋势显著降低。相反，含有四个氨基的四苯基卟啉的存在仅对纤维的形态略有影响，对胰岛素聚集产率的影响较弱（约 44%降低）。这是由于 5,10,15,20-（四-4-羧基苯基）卟啉的芳香族羧基能够与互补的蛋白质结合基团相互作用，从而稳定超分子复合物。对于 5,10,15,20-（四-4-氨基苯基）卟啉，在蛋白质聚集反应的酸性介质中发生完全质子化；这导致 TPPN4 的高正电荷（等于或接近+6），从而导致库仑排斥对 TPPN4 与胰岛素相互作用的贡献更高。TPPN4 的抑制效果较低的另一个可能机制可能是与后者相比，TPPN4 与胰岛素基团形成氢键的可能性受到更多限制。还表明，无金属、含 Pd 和 Cu 的四苯基卟啉没有外围取代基对蛋白质自组装的影响几乎相同。我们认为这是由于这些金属原子的配位饱和。
