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.
Thanks are due to the University of Aveiro, FCT/MEC,
Centro 2020 and Portugal2020, the COMPETE Program, and
the European Union (FEDER Program) via the financial
support to the research units LAQV-REQUIMTE (UIDB/50006/2020), IBiMED (UID/BIM/04501/2019) and CICECO-
Aveiro Institute of Materials (UID/CTM/50011/2019),
financed by national funds through the FCT/MCTES, to the
Portuguese NMR Network, to the ThiMES Project (POCI-01-
0145-FEDER-016630), and to the PAGE Project “Protein
Aggregation Across the Lifespan” (CENTRO-01-0145-
FEDER-000003), including postdoctoral grants to H.M.T.A.
(BPD/UI98/4861/2017) and R.N.d.S. (BPD/UI98/6327/2018). M.P. was supported by Ph.D. Grant SFRH/BD/135655/2018. A.R.S. and S.G. were supported by national
funds (OE) through FCT, I.P., in the scope of the framework
contract foreseen in numbers 4, 5, and 6 of Article 23 of the
Decree-Law 57/2016 of August 29, changed by Law 57/2017
of July 19. Microphotographs were acquired in the LiM facility
of iBiMED/UA, a member of the Portuguese Platform of
BioImaging (PPBI) (POCI-01-0145-FEDER-022122).
