title: 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.
authors.affiliation: Department of Biochemistry, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Velander
authors.affiliation: Department of Biochemistry, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Henderson
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors.forename: Shijun
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA; Center for Drug Discovery, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA; School of Neuroscience, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Bevan
authors.affiliation: Department of Biochemistry, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA; Center for Drug Discovery, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA; School of Neuroscience, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA; Translational Obesity Research Center, Virginia Polytechnic Institute & State University, Blacksburg, VA 24061, USA. Electronic address: binxu@vt.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Xu
mesh_terms: D058227:Amyloidogenic Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000686:Amyloidosis / Q000178:diet therapy / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D000072001:Diet, Healthy; D019587:Dietary Supplements; D015195:Drug Design; D055808:Drug Discovery; D015507:Drugs, Investigational / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D018697:Nootropic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D059808:Polyphenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D066263:Protein Aggregation, Pathological / Q000178:diet therapy / Q000188:drug therapy / Q000517:prevention & control
chemical_list: D058227:Amyloidogenic Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001688:Biological Products; D002614:Chelating Agents; D015507:Drugs, Investigational; D005419:Flavonoids; D018697:Nootropic Agents; D059808:Polyphenols
keywords: Amyloid inhibitor; Covalent mechanisms; Inhibition mechanisms; Natural products; Non-covalent mechanisms