Decreasing amyloid toxicity through an increased rate of aggregation

Sonzini, Silvia; Stanyon, Helen F.; Scherman, Oren A.

doi:10.1039/c6cp06765d

Cited by 25 publications

(23 citation statements)

References 55 publications

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“…It should be noted that CB [7] and CB [8] showedn ot oxic or nutrient effect on N2A cells ( Figure S9, Supporting Information). [18,20] As af urther validation,w ee xploredo ther possible inhibition mechanisms besides fibril-end binding to see whether they can explain the data. Here, three additional mechanisms, inhibition of elongation, primary nucleation and secondary nucleation, were considered, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…These observations were consistent with our fibril‐end binding based inhibition mechanism, since far less toxic mature fibrils would be formed in the presence of CBs. It should be noted that CB[7] and CB[8] showed no toxic or nutrient effect on N2A cells (Figure S9, Supporting Information) …”

Section: Resultsmentioning

confidence: 99%

“…Besides CB [7],c ucurbit [8]uril (CB [8]),w hich could bind with two FGG motifs [19] with a K ter of 1:5 Â 10 11 M À2 , was also examined (Figure 1, Figure S1). Although it was previously reported that CB [8] might increase the aggregationo f Ab 1-42 , [20] our results showedt hat both CB [7] and CB [8] inhibited the aggregation of Ab 4-40 with greater capability than Ab 1-40 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Differential Modulation of the Aggregation of N‐Terminal Truncated Aβ using Cucurbiturils

Gao

Yang

Zhao

et al. 2018

Chemistry A European J

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Modulating the aggregation of Aβ has long been considered to be one of the potential methods to treat Alzheimer's disease (AD). It has been found that different Aβ species, including N-terminal truncated or/and modified Aβ, co-exist in the brain of AD patients. Yet, there is currently little detailed work about the specific modulation of these Aβ species which hinders us to understand their roles in patients' brain. Using thioflavin T (ThT) kinetics and transmission electron microscope, here we showed that cucurbit[7]uril and cucurbit[8]uril could inhibit the aggregation of both Aβ and Aβ through host-guest interactions. Chemical kinetics analysis suggested that this happened through inhibiting the elongation process by binding with fibril ends. In addition, cucurbiturils showed greater capability on the inhibition of Aβ than Aβ , which was possibly due to the N-terminal phenylalanine residue of Aβ . Our work provided new insights for the development of host-guest chemistry based inhibitors for the aggregation of different Aβ species.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential Modulation of the Aggregation of N‐Terminal Truncated Aβ using Cucurbiturils

Gao

Yang

Zhao

et al. 2018

Chemistry A European J

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“…The small molecule trodusquemine, for example, can modulate the aggregation process of Aβ42 and by redirecting it toward the formation of off-pathway non-toxic aggregates ( Limbocker et al, 2019 ). Furthermore, strategies aimed at reducing the populations of oligomers by speeding up the aggregation process have also been proposed ( Bieschke et al, 2011 ; Civitelli et al, 2016 ; Sonzini et al, 2017 ). Along these lines, we show here that our rationally designed bicyclic peptides prevent the conversion of Aβ42 assemblies into fibrillar structure.…”

Section: Introductionmentioning

confidence: 99%

Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies Into Fibrillar Structures

et al. 2021

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There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer’s disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13–42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.

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“…Therefore, some therapeutic strategies aim at decreasing the concentrations of these oligomeric species by delaying or preventing their formation 32,35,37,[39][40][41][42][43][44] . In addition, strategies based on reducing the concentration of toxic oligomers by enhancing the rate of aggregation have also been proposed [45][46][47] . In particular, several attempts have also focused on redirecting the amyloid aggregation towards off-pathway species of lower toxicity, which could be in principle more safely removed by clearance mechanisms such as microglia-mediated phagocytosis or autophagy.…”

mentioning

confidence: 99%

A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

Ikenoue

Aprile

Sormanni

et al. 2020

Sci Rep

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Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

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Decreasing amyloid toxicity through an increased rate of aggregation

Abstract: While it has been reported that wild type Amyloid β (1–42) aggregates are highly toxic, we demonstrate that addition of a discrete macrocyclic host molecule, cucurbit[8]uril, increases the aggregation rate of the peptide but substantially reduces its toxicity.

Cited by 25 publications

References 55 publications

Differential Modulation of the Aggregation of N‐Terminal Truncated Aβ using Cucurbiturils

Differential Modulation of the Aggregation of N‐Terminal Truncated Aβ using Cucurbiturils

Rationally Designed Bicyclic Peptides Prevent the Conversion of Aβ42 Assemblies Into Fibrillar Structures

A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

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