Alzheimer’s disease (AD) is one of the leading causes of death in the US, with an estimated 5.3 million Americans suffering this illness. AD has been consistently associated with misfolding and aggregation of the amyloid-b (Ab) peptide in neurons. Ab is a mostly unstructured peptide of 39 to 42 amino acids in length, which can form soluble (oligomers) and insoluble (fibrils) aggregates. Fibrillar aggregates have a cross-b spine, with a relatively defined structure, and also large, random coiled regions. The intrinsic degree of disorder in these Ab structures makes it difficult to study their structure and interactions with small molecules using traditional laboratory techniques such as X-ray diffraction and nuclear magnetic resonance (NMR). Yet, molecular structural information on how small molecules bind to Ab is needed for developing better diagnostics and drugs that directly act on the aggregates to diminish their deleterious effect on neurons. Here we will present our second-generation probes for studying Ab that are based on Re(I) carbonyl dipyridophenazine complexes. This complex presents unprecedented properties for labeling amyloid aggregates, which involve secondary light switching and selective labeling. We have found that amyloid fibrils photooxidate in a particular amino acid that correlates with the binding place of the metal complex. In addition, we discovered that rhenium complexes can photooxidize amyloid monomers on amino acids that are different from those in the fibrils suggesting a different binding mechanism. We will discuss how finding these photooxidation can help in elucidating molecular binding sites in soluble and insoluble Ab structures. These photochemical modifications have a profound effect on the folding landscape, as well as the self-assembly and stability of amyloid aggregates.

Elucidating binding sites in amyloid-? using photoactive rhenium(I) dipyridophenazine complexes

2019 Spring National Meeting

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