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Specific aromatic foldamers potently inhibit spontaneous and seeded Aβ42 and Aβ43 fibril assembly.

Seither KM, McMahon HA, Singh N, Wang H, Cushman-Nick M, Montalvo GL, DeGrado WF, Shorter J - Biochem. J. (2014)

Bottom Line: Ac-Sal-(Lys-Sal)3-CONH2 and Sal-(Lys-Sal)3-CONH2 selectively inhibited Aβ42 fibrillization, but were ineffective against Aβ43, an overlooked species that is highly neurotoxic and frequently deposited in AD brains.We establish that inhibitors of Aβ42 fibrillization do not necessarily inhibit Aβ43 fibrillization.Moreover, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibits formation of toxic Aβ conformers and seeding activity, properties that could have therapeutic utility.

View Article: PubMed Central - PubMed

Affiliation: *Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.

ABSTRACT
Amyloid fibrils are self-propagating entities that spread pathology in several devastating disorders including Alzheimer's disease (AD). In AD, amyloid-β (Aβ) peptides form extracellular plaques that contribute to cognitive decline. One potential therapeutic strategy is to develop inhibitors that prevent Aβ misfolding into proteotoxic conformers. Here, we design specific aromatic foldamers, synthetic polymers with an aromatic salicylamide (Sal) or 3-amino benzoic acid (Benz) backbone, short length (four repetitive units), basic arginine (Arg), lysine (Lys) or citrulline (Cit) side chains, and various N- and C-terminal groups that prevent spontaneous and seeded Aβ fibrillization. Ac-Sal-(Lys-Sal)3-CONH2 and Sal-(Lys-Sal)3-CONH2 selectively inhibited Aβ42 fibrillization, but were ineffective against Aβ43, an overlooked species that is highly neurotoxic and frequently deposited in AD brains. By contrast, (Arg-Benz)4-CONH2 and (Arg-Sal)3-(Cit-Sal)-CONH2 prevented spontaneous and seeded Aβ42 and Aβ43 fibrillization. Importantly, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibited formation of toxic Aβ42 and Aβ43 oligomers and proteotoxicity. None of these foldamers inhibited Sup35 prionogenesis, but Sal-(Lys-Sal)3-CONH2 delayed aggregation of fused in sarcoma (FUS), an RNA-binding protein with a prion-like domain connected with amyotrophic lateral sclerosis and frontotemporal dementia. We establish that inhibitors of Aβ42 fibrillization do not necessarily inhibit Aβ43 fibrillization. Moreover, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibits formation of toxic Aβ conformers and seeding activity, properties that could have therapeutic utility.

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Overview of aromatic foldamer structureThe core foldamer structure is shown in the dashed box, which can be decorated with different moieties at X-, R-, Y- and Z-positions indicated on the periphery. Foldamers possess an aromatic Sal or Benz backbone (Y=OMe or H), Arg, Lys or Cit side chains (R=Arg, Lys or Cit), short length (two to four repetitive units) and various N- (X=NH2 or Ac) and C- (Z=NH2, OH, OMe or β-Ala) terminal groups.
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Figure 1: Overview of aromatic foldamer structureThe core foldamer structure is shown in the dashed box, which can be decorated with different moieties at X-, R-, Y- and Z-positions indicated on the periphery. Foldamers possess an aromatic Sal or Benz backbone (Y=OMe or H), Arg, Lys or Cit side chains (R=Arg, Lys or Cit), short length (two to four repetitive units) and various N- (X=NH2 or Ac) and C- (Z=NH2, OH, OMe or β-Ala) terminal groups.

Mentions: As potential inhibitors of Aβ42 and Aβ43 amyloidogenesis, we explored aromatic foldamers (Figures 1 and 2). Some of these foldamers were originally synthesized as inhibitors of heparin and are rich in aromatic and positively charged groups [55]. They possess an aromatic salicylamide (Sal) or 3-amino benzoic acid (Benz) backbone (Figure 1; Y=OMe or H), lysine (Lys), arginine (Arg) or citrulline (Cit) side chains (Figure 1; R=Lys, Arg or Cit), short length (two to four repetitive units) (Figure 1) and various N- (Figure 1; X=NH2 or COMe [Ac]) and C-(Figure 1; Z=NH2, OH, OMe or β-Ala) terminal groups. We selected this design for four reasons. First, the aromatic backbone is similar to ones employed by Nowick et al. [42,51–53] in protein aggregation inhibitors. Secondly, interactions between aromatic residues within short amyloidogenic peptides mediate molecular recognition during fibrillization [59]. Moreover, polyphenols such as (−)-epigallocatechin-3-gallate (EGCG) inhibit amyloidogenesis and prevent cytotoxicity [57,59–61]. Thus, the aromatic foldamer spine might antagonize aromatic interactions critical for fibrillization. Thirdly, the aromatic foldamers investigated are approximately the same length (two to four repetitive units) as steric zipper hexapeptides that form amyloid [19]. Finally, basic side chains, particularly arginine exert hydrotropic effects and prevent protein aggregation [62].


Specific aromatic foldamers potently inhibit spontaneous and seeded Aβ42 and Aβ43 fibril assembly.

Seither KM, McMahon HA, Singh N, Wang H, Cushman-Nick M, Montalvo GL, DeGrado WF, Shorter J - Biochem. J. (2014)

Overview of aromatic foldamer structureThe core foldamer structure is shown in the dashed box, which can be decorated with different moieties at X-, R-, Y- and Z-positions indicated on the periphery. Foldamers possess an aromatic Sal or Benz backbone (Y=OMe or H), Arg, Lys or Cit side chains (R=Arg, Lys or Cit), short length (two to four repetitive units) and various N- (X=NH2 or Ac) and C- (Z=NH2, OH, OMe or β-Ala) terminal groups.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4209162&req=5

Figure 1: Overview of aromatic foldamer structureThe core foldamer structure is shown in the dashed box, which can be decorated with different moieties at X-, R-, Y- and Z-positions indicated on the periphery. Foldamers possess an aromatic Sal or Benz backbone (Y=OMe or H), Arg, Lys or Cit side chains (R=Arg, Lys or Cit), short length (two to four repetitive units) and various N- (X=NH2 or Ac) and C- (Z=NH2, OH, OMe or β-Ala) terminal groups.
Mentions: As potential inhibitors of Aβ42 and Aβ43 amyloidogenesis, we explored aromatic foldamers (Figures 1 and 2). Some of these foldamers were originally synthesized as inhibitors of heparin and are rich in aromatic and positively charged groups [55]. They possess an aromatic salicylamide (Sal) or 3-amino benzoic acid (Benz) backbone (Figure 1; Y=OMe or H), lysine (Lys), arginine (Arg) or citrulline (Cit) side chains (Figure 1; R=Lys, Arg or Cit), short length (two to four repetitive units) (Figure 1) and various N- (Figure 1; X=NH2 or COMe [Ac]) and C-(Figure 1; Z=NH2, OH, OMe or β-Ala) terminal groups. We selected this design for four reasons. First, the aromatic backbone is similar to ones employed by Nowick et al. [42,51–53] in protein aggregation inhibitors. Secondly, interactions between aromatic residues within short amyloidogenic peptides mediate molecular recognition during fibrillization [59]. Moreover, polyphenols such as (−)-epigallocatechin-3-gallate (EGCG) inhibit amyloidogenesis and prevent cytotoxicity [57,59–61]. Thus, the aromatic foldamer spine might antagonize aromatic interactions critical for fibrillization. Thirdly, the aromatic foldamers investigated are approximately the same length (two to four repetitive units) as steric zipper hexapeptides that form amyloid [19]. Finally, basic side chains, particularly arginine exert hydrotropic effects and prevent protein aggregation [62].

Bottom Line: Ac-Sal-(Lys-Sal)3-CONH2 and Sal-(Lys-Sal)3-CONH2 selectively inhibited Aβ42 fibrillization, but were ineffective against Aβ43, an overlooked species that is highly neurotoxic and frequently deposited in AD brains.We establish that inhibitors of Aβ42 fibrillization do not necessarily inhibit Aβ43 fibrillization.Moreover, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibits formation of toxic Aβ conformers and seeding activity, properties that could have therapeutic utility.

View Article: PubMed Central - PubMed

Affiliation: *Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, 805b Stellar-Chance Laboratories, 422 Curie Boulevard, Philadelphia, PA 19104, U.S.A.

ABSTRACT
Amyloid fibrils are self-propagating entities that spread pathology in several devastating disorders including Alzheimer's disease (AD). In AD, amyloid-β (Aβ) peptides form extracellular plaques that contribute to cognitive decline. One potential therapeutic strategy is to develop inhibitors that prevent Aβ misfolding into proteotoxic conformers. Here, we design specific aromatic foldamers, synthetic polymers with an aromatic salicylamide (Sal) or 3-amino benzoic acid (Benz) backbone, short length (four repetitive units), basic arginine (Arg), lysine (Lys) or citrulline (Cit) side chains, and various N- and C-terminal groups that prevent spontaneous and seeded Aβ fibrillization. Ac-Sal-(Lys-Sal)3-CONH2 and Sal-(Lys-Sal)3-CONH2 selectively inhibited Aβ42 fibrillization, but were ineffective against Aβ43, an overlooked species that is highly neurotoxic and frequently deposited in AD brains. By contrast, (Arg-Benz)4-CONH2 and (Arg-Sal)3-(Cit-Sal)-CONH2 prevented spontaneous and seeded Aβ42 and Aβ43 fibrillization. Importantly, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibited formation of toxic Aβ42 and Aβ43 oligomers and proteotoxicity. None of these foldamers inhibited Sup35 prionogenesis, but Sal-(Lys-Sal)3-CONH2 delayed aggregation of fused in sarcoma (FUS), an RNA-binding protein with a prion-like domain connected with amyotrophic lateral sclerosis and frontotemporal dementia. We establish that inhibitors of Aβ42 fibrillization do not necessarily inhibit Aβ43 fibrillization. Moreover, (Arg-Sal)3-(Cit-Sal)-CONH2 inhibits formation of toxic Aβ conformers and seeding activity, properties that could have therapeutic utility.

Show MeSH
Related in: MedlinePlus