Thiophene‐Based Ligands: Design, Synthesis and Their Utilization for Optical Assignment of Polymorphic‐Disease‐Associated Protein Aggregates

Conformation-sensitive thiophene-based ligands have emerged as a class of molecular tools for efficient optical imaging of disease-associated protein aggregates. This review summarizes the design and chemical evolution of thiophene-based ligands, as well as describes how this class of ligands has been used for fluorescent assignment of polymorphic disease-associated protein aggregates.

Abstract

The development of ligands for detecting protein aggregates is of great interest, as these aggregated proteinaceous species are the pathological hallmarks of several devastating diseases, including Alzheimer's disease. In this regard, thiophene-based ligands have emerged as powerful tools for fluorescent assessment of these pathological entities. The intrinsic conformationally sensitive photophysical properties of poly- and oligothiophenes have allowed optical assignment of disease-associated protein aggregates in tissue sections, as well as real-time in vivo imaging of protein deposits. Herein, we recount the chemical evolution of different generations of thiophene-based ligands, and exemplify their use for the optical distinction of polymorphic protein aggregates. Furthermore, the chemical determinants for achieving a superior fluorescent thiophene-based ligand, as well as the next generation of thiophene-based ligands targeting distinct aggregated species are described. Finally, the directions for future research into the chemical design of thiophene-based ligands that can aid in resolving the scientific challenges around protein aggregation diseases are discussed.

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