Therapeutic properties of luminescent Ru (II) to amyloid proteins fibrillation

Abstract

Type 2 Diabetes Mellitus (DM2) is a metabolic disease that reaches epidemic proportions worldwide. Insulin and amylin (amyloid polypeptide from human pancreatic islets (IAPP) are amyloid proteins secreted by pancreatic b cells. While insulin is associated with blood glycemic control, amylin has led to the development of DM2. Although several studies indicate that amylin toxicity comes from its aggregation process and that an interaction with insulin inhibits aggregation and toxicity, the discussion of these interactions and effects at the molecular level is still unknown. Recent studies of the interaction of the cis-[Ru(phen)2(Apy)2]2+, (RuApy) complex, in which phen = 1,10-phenanthroline and 3,4-Apy = 3,4-aminopyridine, with bovine insulin during its aggregation process performed by Lorena during her master's degree showed that this complex is a luminescent probe sensitive to the aggregation of this protein. These results motivated us to (1) explore the process of aggregation of amylin in the absence and presence of insulin (native, oligomeric and fibrillar) by varying the concentration of insulin and (2) determine how these conditions interfere with amylin aggregation. For this, we intend to use RuApy luminescent responses to map the conformational changes during aggregation. Since the p-p stacking interactions between proteins can favor the aggregation process by stabilizing fibril forms and hydrogen bonds we intend (3) to synthesize the [Ru(phen)2(pPDIp)]2+ complex, where pPDIp = 1,10-phenanthroline derivatized with a naphthalenediimide group, with the intention of increasing non-covalent interactions with the aromatic aminoacid residues of amylin and thus (4) exploring the inhibitory effect of amylin aggregation. The studies will be carried out using UV-vis spectroscopy, luminescence (steady state and time resolved), fluorescence microscopy, circular dichroism, and mass spectrometry. The studies proposed in this project were designed to contribute to the elucidation of insulin-amylin interactions such as those associated with DM2 and to recognize the potential of the RuApy and [Ru(phen)2(pPDIp)]2+ complexes as luminescent and therapeutic sensors to amyloid proteins. (AU)