Design strategies for anti-amyloid agents

Mason, Jody M.; Kokkoni, Nicoleta; Stott, Kelvin; Doig, Andrew J.

doi:10.1016/s0959-440x(03)00100-3

Cited by 117 publications

(134 citation statements)

References 51 publications

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“…In recent years, interest has arisen in exploring the potential of therapeutic strategies that interfere with amyloid formation by stabilizing the native state of the precursor protein (42)(43)(44)(45). TTR aggregation has been a model system for this approach, because small molecules, including the nonsteroidal anti-inflammatory drug diflunisal and many of its derivatives, are reported to stabilize the native tetrameric structure (31,32,46).…”

Section: Discussionmentioning

confidence: 99%

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Kingsbury

Laue

Klimtchuk

et al. 2008

Journal of Biological Chemistry

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Transthyretin (TTR) is normally a stable plasma protein.However, in cases of familial TTR-related amyloidosis and senile systemic amyloidosis (SSA), TTR is deposited as amyloid fibrils, leading to organ dysfunction and possibly death. The mechanism by which TTR undergoes the transition from stable, soluble precursor to insoluble amyloid fibril and the factors that promote this process are largely undetermined. Most models involve the dissociation of the native TTR tetramer as the initial step. It is largely accepted that the TTR gene mutations associated with TTR-related amyloidosis lead to the expression of variant proteins that are intrinsically unstable and prone to aggregation. It has been suggested that amyloidogenicity may be conferred to wild-type TTR (the form deposited in SSA) by chemical modification of the lone cysteine residue (Cys 10 ) through mixed disulfide bonds. S-Sulfonation and S-cysteinylation are prevalent TTR modifications physiologically, and studies have suggested their ability to modulate the structure of TTR under denaturing conditions. In the present study, we have used fluorescencedetected sedimentation velocity to determine the effect of S-sulfonate and S-cysteine on the quaternary structural stability of fluorophore-conjugated recombinant TTR under nondenaturing conditions. We determined that S-sulfonation stabilized TTR tetramer stability by a factor of 7, whereas S-cysteinylation enhanced dissociation by 2-fold with respect to the unmodified form. In addition, we report the direct observation of tetramer stabilization by the potential therapeutic compound diflunisal. Finally, as proof of concept, we report the sedimentation of TTR in serum and the qualitative assessment of the resulting data.

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Section: Discussionmentioning

confidence: 99%

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

Kingsbury

Laue

Klimtchuk

et al. 2008

Journal of Biological Chemistry

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“…A number of low-molecular-mass A␤ aggregation inhibitors have been identified by use of screens of compound libraries as well as rational design strategies. The resulting inhibitors include such chemically diverse compounds as curcumin, inositol, and nicotine (9,10). The screens have identified inhibitors of fibril formation that similarly to the rationally designed inhibitors are predicted to bind to A␤ in an elongated, ␤-strand-like conformation and prevent its polymerization.…”

mentioning

confidence: 99%

α-Helix targeting reduces amyloid-β peptide toxicity

Nerelius

Sandegren

Sargsyan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

128

150

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The amyloid-␤ peptide (A␤) can generate cytotoxic oligomers, and their accumulation is thought to underlie the neuropathologic changes found in Alzheimer's disease. Known inhibitors of A␤ polymerization bind to undefined structures and can work as nonspecific aggregators, and inhibitors that target conformations that also occur in larger A␤ assemblies may even increase oligomerderived toxicity. Here we report on an alternative approach whereby ligands are designed to bind and stabilize the 13-26 region of A␤ in an ␣-helical conformation, inspired by the postulated A␤ native structure. This is achieved with 2 different classes of compounds that also reduce A␤ toxicity to cells in culture and to hippocampal slice preparations, and that do not show any nonspecific aggregatory properties. In addition, when these inhibitors are administered to Drosophila melanogaster expressing human A␤ 1-42 in the central nervous system, a prolonged lifespan, increased locomotor activity, and reduced neurodegeneration is observed. We conclude that stabilization of the central A␤ ␣-helix counteracts polymerization into toxic assemblies and provides a strategy for development of specific inhibitors of A␤ polymerization.amyloid fibrils ͉ neurodegenerative disease ͉ protein misfolding ͉ Alzheimer's disease A lzheimer's disease is a progressive neurodegenerative disorder that is characterized by cerebral extracellular amyloid plaques and intracellular neurofibrillary tangles (1). Classically, the amyloid cascade hypothesis (2) states that Alzheimer's disease is caused by fibril and plaque formation of amyloid-␤ peptide (A␤) in the central nervous system. More recently, the hypothesis has been modified to include A␤ assemblies of sizes intermediate to monomeric and fibrillar forms, which today are considered to be the main source of cytotoxicity (3). Such A␤ assemblies include low-number oligomers and larger assemblies known as protofibrils, globulomers, Alzheimer's disease diffusible ligands, or A␤*56 (4-7). A␤ is cleaved from an integral membrane protein, the amyloid ␤ precursor protein (A␤PP), predominantly as a 40-residue peptide (A␤ 1-40 ). In addition, a C-terminally elongated 42-residue version can be excised (A␤ 1-42 ); it is this longer variant that is the main constituent of parenchymal amyloid deposits (8).The link between A␤ aggregation and Alzheimer's disease implies that inhibitors of this process should be able to slow down disease progression. A number of low-molecular-mass A␤ aggregation inhibitors have been identified by use of screens of compound libraries as well as rational design strategies. The resulting inhibitors include such chemically diverse compounds as curcumin, inositol, and nicotine (9, 10). The screens have identified inhibitors of fibril formation that similarly to the rationally designed inhibitors are predicted to bind to A␤ in an elongated, ␤-strand-like conformation and prevent its polymerization. A potential problem with this strategy is that blocking the later stages of fibril formation will favor t...

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“…107 These peptidomimetic molecules by themselves or with further modifications provide a class of reagents that may help elucidate the mechanism of amyloid aggregation, perhaps by trapping intermediates, as well as providing inroads into the design of diagnostic and therapeutic reagents.…”

Section: D-amino Acid Peptidesmentioning

confidence: 99%

Molecules that Target beta‐Amyloid

2007

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The devastating effects of Alzheimer’s and related amyloidogenic diseases have inspired the synthesis and evaluation of numerous ligands to understand the molecular mechanism of the aggregation of the beta‐amyloid peptide. Our review focuses on the current knowledge in this field with respect to molecules that have been demonstrated to interact with either oligomeric or fibrillar forms of the beta‐amyloid peptide. We describe natural proteins, peptides, peptidomimetics, and small molecules that have been found to interfere with beta‐amyloid aggregation. We also detail recent efforts in selecting molecules that target beta‐amyloid isolated from antibody, protein, and peptide libraries. These new molecules will likely aid in deciphering the details of the aggregation pathway for the beta‐amyloid peptide and provide reagents that may stabilize relevant oligomeric intermediates which likely have bearing on the pathophysiology of Alzheimer’s disease. Moreover, the described anti‐amyloid molecular toolbox will also provide an avenue for designing new diagnostic and therapeutic reagents.

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Design strategies for anti-amyloid agents

Cited by 117 publications

References 51 publications

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

The Modulation of Transthyretin Tetramer Stability by Cysteine 10 Adducts and the Drug Diflunisal

α-Helix targeting reduces amyloid-β peptide toxicity

Molecules that Target beta‐Amyloid

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