title: Increase of Positive Net Charge and Conformational Rigidity Enhances the Efficacy of d-Enantiomeric Peptides Designed to Eliminate Cytotoxic Aβ Species.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder and the most common type of dementia. Until now, there is no curative therapy available. Previously, we selected the amyloid-beta (Aβ) targeting peptide D3 consisting of 12 d-enantiomeric amino acid residues by mirror image phage display as a potential drug candidate for the treatment of AD. In the current approach, we investigated the optimization potential of linear D3 with free C-terminus (D3COOH) by chemical modifications. First, the impact of the net charge was investigated and second, cyclization was introduced which is a well-known tool for the optimization of peptides for enhanced target affinity. Following this strategy, three D3 derivatives in addition to D3COOH were designed: C-terminally amidated linear D3 (D3CONH2), cyclic D3 (cD3), and cyclic D3 with an additional arginine residue (cD3r) to maintain the net charge of linear D3CONH2. These four compounds were compared to each other according to their binding affinities to Aβ(1-42), their efficacy to eliminate cytotoxic oligomers, and consequently their potency to neutralize Aβ(1-42) oligomer induced neurotoxicity. D3CONH2 and cD3r versions with equally increased net charge showed superior properties over D3COOH and cD3, respectively. The cyclic versions showed superior properties compared to their linear version with equal net charge, suggesting cD3r to be the most efficient compound among these four. Indeed, treatment of the transgenic AD mouse model Tg-SwDI with cD3r significantly enhanced spatial memory and cognition of these animals as revealed by water maze performance. Therefore, charge increase and cyclization imply suitable modification steps for an optimization approach of the Aβ targeting compound D3.
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.
authors.forename: Tamar
authors.initials: T
authors.lastname: Ziehm
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Brener
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham (UAB) , Birmingham, Alabama 35233, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: van Groen
authors.affiliation: Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham (UAB) , Birmingham, Alabama 35233, United States.
authors.forename: Inga
authors.initials: I
authors.lastname: Kadish
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Frenzel
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Tusche
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Kutzsche
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Reiß
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Gremer
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany.
authors.forename: Luitgard
authors.initials: L
authors.lastname: Nagel-Steger
authors.affiliation: Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich , 52425 Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf , 40225 Düsseldorf, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Willbold
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008968:Molecular Conformation / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry; D010446:Peptide Fragments / Q000378:metabolism* / Q000633:toxicity* / Q000648:ultrastructure; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism / Q000627:therapeutic use*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016207:Cytokines; C404517:D3 compound; C534952:D3 peptide; D009842:Oligopeptides; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; amyloid-beta; charge increase; cyclization; d-enantiomeric peptides; drug discovery