Natural product-based amyloid inhibitors

Abstract

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned.

Keywords: Amyloid inhibitor; Covalent mechanisms; Inhibition mechanisms; Natural products; Non-covalent mechanisms.

Fig. 1

Chemical structures of identified natural product protein amyloid inhibitors. These inhibitors are classified as flavonoids, other phenolic compounds, and additional natural compounds including quinones, pyridines, aldehydes, sugar alcohols, terpenes, etc. In each category, compounds are listed alphabetically.

Fig. 1

Chemical structures of identified natural product protein amyloid inhibitors. These inhibitors are classified as flavonoids, other phenolic compounds, and additional natural compounds including quinones, pyridines, aldehydes, sugar alcohols, terpenes, etc. In each category, compounds are listed alphabetically.

Fig. 1

Chemical structures of identified natural product protein amyloid inhibitors. These inhibitors are classified as flavonoids, other phenolic compounds, and additional natural compounds including quinones, pyridines, aldehydes, sugar alcohols, terpenes, etc. In each category, compounds are listed alphabetically.

Fig. 2

Schematic representations of several proposed mechanisms between inhibitors and amyloid proteins. (A) Non-covalent interaction mechanisms with curcumin as an example. Left panel: The planar curcumin molecule is depicted by a cartoon schematic within the cross beta spine of an octomeric fibrillar backbone. This representation is based on the structural model of curcumin bound to the VQIVYK segment from the tau protein as well as MD simulation results of curcumin docking onto Aβ hexapeptide KLVFFA [30]. Right panel: key non-covalent interactions occur within the cross beta spine of full-length amyloid β peptide and curcumin, as depicted from a recent MD simulation study [32]. His14 undergoes π–π stacking (dotted line) with one end of the aromatic heads of curcumin, which is also positioned in a hydrophobic area near Phe20 (bottom right). The central keto-enol functional groups and as well as the aromatic head (bottom left) undergo hydrogen bonding with lysine residues located on opposite sides of the cross beta spine (hashed lines). Additionally, π–alkyl interactions (depicted by dotted line) were seen between the aromatic head of curcumin (bottom left) and Val18 residues. (B) Covalent interaction mechanisms. Small molecule natural compounds containing electrophilic functional groups such as o-quinones and aldehydes form covalent adducts with amyloidogenic proteins and prevent amyloid formation. (Top panel) Taxifolin forms covalent adducts with the side chain amine group of lysine in Aβ_1-42 via Schiff base formation via o-quinone intermediates. (Middle and Lower panels) Tau is covalently modified by the aldehyde functional groups in the case of cinnamaldehyde (middle panel) and oleocanthal (lower panel) via Michael addition and Schiff base respectively. Such conjugation prevents protein amyloid growth and formation.