Designed Hairpin Peptides
Interfere with Amyloidogenesis Pathways: Fibril Formation and Cytotoxicity
Inhibition, Interception of the Preamyloid State
Posted on 2011-09-27 - 00:00
Hairpin peptides bearing cross-strand Trp-Trp and Tyr-Tyr
pairs at non-H-bonded strand sites modulate the aggregation of two
unrelated amyloidogenic systems, human pancreatic amylin (hAM) and
α-synuclein (α-syn), associated with type II diabetes
and Parkinson’s disease, respectively. In the case of hAM,
we have previously reported that inhibition of amyloidogenesis is
observed as an increase in the lag time to amyloid formation and a
diminished thioflavin (ThT) fluorescence response. In this study,
a reduced level of hAM fibril formation is confirmed by transmission
electron microscopy imaging. Several of the hairpins tested were significantly
more effective inhibitors than rat amylin. Moreover, a marked inhibitory
effect on hAM-associated cytotoxicity by the more potent hairpin peptide
is demonstrated. In the case of α-syn, the dominant effect of
active hairpins was, besides a weakened ThT fluorescence response,
the earlier appearance of insoluble aggregates that do not display
amyloid characteristics with the few fibrils observed having abnormal
morphology. We attribute the alteration of the α-synuclein aggregation
pathway observed to the capture of a preamyloid state and diversion
to nonamyloidogenic aggregates. These β-hairpins represent a
new class of amyloid inhibitors that bear no sequence similarity to
the amyloid-producing polypeptides that are inhibited. A mechanistic
rationale for these effects is proposed.
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Huggins, Kelly
N. L.; Bisaglia, Marco; Bubacco, Luigi; Tatarek-Nossol, Marianna; Kapurniotu, Aphrodite; Andersen, Niels H. (2016). Designed Hairpin Peptides
Interfere with Amyloidogenesis Pathways: Fibril Formation and Cytotoxicity
Inhibition, Interception of the Preamyloid State. ACS Publications. Collection. https://doi.org/10.1021/bi200760h
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AUTHORS (6)
KH
Kelly
N. L. Huggins
MB
Marco Bisaglia
LB
Luigi Bubacco
MT
Marianna Tatarek-Nossol
AK
Aphrodite Kapurniotu
NA
Niels H. Andersen
KEYWORDS
preamyloid statenonamyloidogenic aggregatesHairpin Peptides InterfereFibril Formationamyloid inhibitorsAmyloidogenesis Pathwayspancreatic amylinamyloidogenic systemsamyloid formationfluorescence responserat amylinThT fluorescence responsePreamyloid StateHairpin peptidestype II diabetessequence similarityCytotoxicity Inhibitiontransmission electron microscopy imaginghairpin peptidedisplay amyloid characteristicssynucleinsynaggregationhAM fibril formation