(E)-6-Methyl-4′-amino-2-styrylquinoline (3) is a small molecule with the proper features to potentially diagnose, deliver therapy and monitor response to therapy in protein misfolding diseases. These features include compound fluorescent emission in the NIR region and its ability to interact with both Aβ and prion fibrils, staining them with high selectivity. Styrylquinoline 3 also inhibits Aβ self-aggregation in vitro and prion replication in the submicromolar range in a cellular context. Furthermore, it is not toxic and is able to cross the blood brain barrier in vitro (PAMPA test).KEYWORDS: Aggregation, protein misfolding diseases, amyloid, fibrillation inhibitors P rotein misfolding diseases (PMD) include a broad range of human disorders characterized by a conformational change of normally expressed proteins, that convert from a physiological soluble monomeric form into oligomeric and fibrillar forms, rich in stable β-sheet regions. 1 These fibrillar aggregates play a pivotal role in neuronal dysfunction and survival, eventually leading to fatal disease. Alzheimer's (AD) and prion diseases (PrD) are prototypical examples of PMD. In these maladies, amyloid-β protein (Aβ) and cellular prion protein (PrP C ), respectively, change their conformations into β-sheet toxic isoforms. In the case of PrD, the toxic isoform known as scrapie prion protein (PrP Sc ) is also infectious. 2 In AD and PrD, the misfolded proteins have been regarded both as neuropathological hallmarks for diagnosis and as therapeutic targets. 2 While the so-called "amyloid hypothesis" in AD has been questioned, a recent interest has arisen in the possibility that all proteins causing neurodegeneration are prions. 2 If confirmed, this hypothesis would profoundly influence the development of diagnostic and therapeutic tools. 2 Many techniques have been employed to detect fibrillar aggregates, including positron emission tomography (PET) 3 and fluorescence spectroscopy. 4 PET is expensive and limited by the narrow isotope availability of the required probes. On the other hand, many fluorescent in vitro staining agents are available such as Congo Red (CR) and Thioflavin T (ThT) but they cannot translate into clinical diagnostic and therapeutic tools 4 because of their low specificity, poor sensitivity, inability to cross the blood brain barrier (BBB) and marked toxicity. 5 Because fluorescence spectroscopy has proven suitable for studying fibrillar aggregates also in vivo, 6−9 there is an urgent need for fluorescent sensors with improved properties.With these concepts in mind, we focused our attention on fluorescent compounds capable of staining Aβ and PrP Sc fibrils and, ideally, of simultaneously blocking their aggregation. To this aim, ideal properties for a therapeutic and diagnostic small molecule should include (1) ability to change fluorescence properties upon binding to fibrils, (2) ability to absorb and emit light in the far red/near-infrared (NIR) region (ca. 600−800 nm), 7 where tissue scattering and absorption is lowest...

Prion diseases are fatal neurodegenerative and infectious disorders for which effective pharmacological tools are not yet available. This unmet challenge and the recently proposed interplay between prion diseases and Alzheimer's have led to a more urgent demand for new antiprion agents. Herein, we report the identification of a novel bifunctional diketopiperazine (DKP) derivative 1 d, which exhibits activity in the low micromolar range against prion replication in ScGT1 cells, while showing low cytotoxicity. Supported by properly addressed molecular modeling studies, we hypothesized that a planar conformation is the major determinant for activity in this class of compounds. Moreover, studies aimed at assessing the mechanism-of-action at the molecular level showed that 1 d might interact directly with recombinant prion protein (recPrP) to prevent its conversion to the pathogenic misfolded prion protein (PrP(Sc))-like form. This investigation suggests that DKP based antiprion compounds can serve as a promising lead scaffold in developing new drugs to combat prion diseases.

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