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Advisor(s)
Abstract(s)
Reversing protein aggregation within cells may be an
important tool to fight protein-misfolding disorders such as Alzheimer’s,
Parkinson’s, and cardiovascular diseases. Here we report the design and
synthesis of a family of steroid−quinoline hybrid compounds based on
the framework combination approach. This set of hybrid compounds
effectively inhibited Aβ1−42 self-aggregation in vitro by delaying the
exponential growth phase and/or reducing the quantity of fibrils in the
steady state. Their disaggregation efficacy was further demonstrated
against preaggregated Aβ1−42 peptides in cellular assays upon their
endocytosis by neuroblastoma cells, as they reverted both the number
and the average area of fibrils back to basal levels. The antiaggregation
effect of these hybrids was further tested and demonstrated in a cellular
model of general protein aggregation expressing a protein aggregation fluorescent sensor. Together, our results show that the new
cholesterol−quinoline hybrids possess wide and marked disaggregation capacities and are therefore promising templates for the
development of new drugs to deal with conformational disorders.
Description
Keywords
Steroid−quinoline hybrids Protein aggregation Amyloid-β (Aβ) peptide Protein misfolding diseases
Citation
Albuquerque, Hélio M.T.; Silva, Raquel Nunes da; Pereira, Marisa; Maia, André; Guieu, Samuel; Soares, Ana Raquel; Santos, Clementina M. M.; Vieira, Sandra I.; Silva, Artur (2022). Steroid–quinoline hybrids for disruption and reversion of protein aggregation processes. ACS Medicinal Chemistry Letters. ISSN 1948-5875. p. 1-6
Publisher
ACS