title: Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation.
abstract: Many globular and natively disordered proteins can convert into amyloid fibrils. These fibrils are associated with numerous pathologies as well as with normal cellular functions, and frequently form during protein denaturation. Inhibitors of pathological amyloid fibril formation could be useful in the development of therapeutics, provided that the inhibitors were specific enough to avoid interfering with normal processes. Here we show that computer-aided, structure-based design can yield highly specific peptide inhibitors of amyloid formation. Using known atomic structures of segments of amyloid fibrils as templates, we have designed and characterized an all-D-amino-acid inhibitor of the fibril formation of the tau protein associated with Alzheimer's disease, and a non-natural L-amino-acid inhibitor of an amyloid fibril that enhances sexual transmission of human immunodeficiency virus. Our results indicate that peptides from structure-based designs can disrupt the fibril formation of full-length proteins, including those, such as tau protein, that lack fully ordered native structures. Because the inhibiting peptides have been designed on structures of dual-β-sheet 'steric zippers', the successful inhibition of amyloid fibril formation strengthens the hypothesis that amyloid spines contain steric zippers.
authors.affiliation: Department of Biological Chemistry, Howard Hughes Medical Institute, UCLA, Box 951970, Los Angeles, California 90095-1570, USA.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Sievers
authors.forename: John
authors.initials: J
authors.lastname: Karanicolas
authors.forename: Howard W
authors.initials: HW
authors.lastname: Chang
authors.forename: Anni
authors.initials: A
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Jiang
authors.forename: Onofrio
authors.initials: O
authors.lastname: Zirafi
authors.forename: Jason T
authors.initials: JT
authors.lastname: Stevens
authors.forename: Jan
authors.initials: J
authors.lastname: Münch
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: David
authors.initials: D
authors.lastname: Eisenberg
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D000682:Amyloid / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D017076:Computer-Aided Design; D015195:Drug Design; D015658:HIV Infections / Q000821:virology; D006860:Hydrogen Bonding; D007700:Kinetics; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D011107:Polylysine / Q000494:pharmacology; D011487:Protein Conformation; D016875:tau Proteins / Q000037:antagonists & inhibitors
chemical_list: D000596:Amino Acids; D000682:Amyloid; D016229:Amyloid beta-Peptides; D010455:Peptides; D016875:tau Proteins; D011107:Polylysine