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Velander P
; Wu L
; Henderson F
; Zhang S
; Bevan DR
; Xu B
Biochem Pharmacol
2017[Sep]; 139
(?): 40-55
PMID28390938
show ga
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.
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