Natural compounds as inhibitors of transthyretin amyloidosis and neuroprotective agents: analysis of structural data for future drug design

Natural compounds, such as plant and fruit extracts have shown neuroprotective effect against neurodegenerative diseases. It has been reported that several natural compounds binding to transthyretin (TTR) can be useful in amyloidosis prevention. TTR is a transporter protein that under physiological condition carries thyroxine (T4) and retinol in plasma and in cerebrospinal fluid (CSF); it also has a neuroprotective role against Alzheimer’s disease (AD). However, TTR also is an amyloidogenic protein responsible for familial amyloid polyneuropathy (FAP) and familial amyloid cardiomyopathy (FAC). The TTR amyloidogenic potential is speeded up by several point mutations. One therapeutic strategy against TTR amyloidosis is the stabilisation of the native tetramer by natural compounds and small molecules. In this review, we examine the natural products that, starting from 2012 to present, have been studied as a stabiliser of TTR tetramer. In particular, we discussed the chemical and structural features which will be helpful for future drug design of new TTR stabilisers

The positive side of the Alzheimer's disease amyloid cross-interactions: The case of the Aβ 1-42 peptide with tau, TTR, CysC, and ApoA1

Alzheimer's disease (AD) represents a progressive amyloidogenic disorder whose advancement is widely recognized to be connected to amyloid-β peptides and Tau aggregation. However, several other processes likely contribute to the development of AD and some of them might be related to protein-protein interactions. Amyloid aggregates usually contain not only single type of amyloid protein, but also other type of proteins and this phenomenon can be rationally explained by the process of protein cross-seeding and co-assembly. Amyloid cross-interaction is ubiquitous in amyloid fibril formation and so a better knowledge of the amyloid interactome could help to further understand the mechanisms of amyloid related diseases. In this review, we discuss about the cross-interactions of amyloid-β peptides, and in particular Aβ1-42, with other amyloids, which have been presented either as integrated part of Aβ neurotoxicity process (such as Tau) or conversely with a preventive role in AD pathogenesis by directly binding to Aβ (such as transthyretin, cystatin C and apolipoprotein A1). Particularly, we will focus on all the possible therapeutic strategies aiming to rescue the Aβ toxicity by taking inspiration from these protein-protein interactions

Antioxidant quercetin 3-O-glycosylated plant flavonols contribute to Transthyretin stabilization

Plants are rich in secondary metabolites, which are often useful as a relevant source of nutraceuticals. Quercetin (QUE) is a flavonol aglycone able to bind Transthyretin (TTR), a plasma protein that under pathological conditions can lose its native structure leading to fibrils formation and amyloid diseases onset. Here, the dual nature of five quercetin 3-O-glycosylated flavonol derivatives, isolated from different plant species, such as possible binders of TTR and antioxidants, was investigated. The crystal structure of 3-O-β-D-galactopyranoside in complex with TTR was solved, suggesting that not only quercetin but also its metabolites can contribute to stabilizing the TTR tetramer

ß-Hairpin mimics containing a piperidine-pyrrolidine scaffold modulate the ß-amyloid aggregation process preserving the monomer species

Alzheimer’s disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of Aβ1-42-amyloid related β-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid β-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of Aβ1-42. According to these peptide sequences, a stable β-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of Aβ1-42 aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. Furthermore, compounds protect against toxic effects of Aβ on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small β-hairpin mimics possessing such a highly efficient anti-aggregation activity. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. The structural elements made in this study provide valuable insights in the understanding of the aggregation process and insights to explore the design of novel acyclic β-hairpin targeting other types of amyloid-forming proteins

Physiological metals can induce conformational changes in transthyretin structure: Neuroprotection or misfolding induction?

Transthyretin (TTR) is a plasma homotetrameric protein that transports thyroxine and retinol. TTR itself, under pathological conditions, dissociates into partially unfolded monomers that aggregate and form fibrils. Metal ions such as Zn2+, Cu2+, Fe2+, Mn2+ and Ca2+ play a controversial role in the TTR amyloidogenic pathway. TTR is also present in cerebrospinal fluid (CSF), where it behaves as one of the major Aβ-binding-proteins. The interaction between TTR and Aβ is stronger in the presence of high concentrations of Cu2+. Crystals of TTR, soaked in solutions of physiological metals such as Cu2+ and Fe2+, but not Mn2+, Zn2+, Fe3+, Al3+, Ni2+, revealed an unusual conformational change. Here, we investigate the effects that physiological metals have on TTR, in order to understand if metals can induce a specific and active conformation of TTR that guides its Aβ-scavenging role. The capability of certain metals to induce and accelerate its amyloidogenic process is also discussed