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Steroid–quinoline hybrids for disruption and reversion of protein aggregation processes

2022Artigo científico Acesso aberto
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dc.contributor.authorAlbuquerque, Hélio
dc.contributor.authorSilva, Raquel Nunes da
dc.contributor.authorPereira, Marisa
dc.contributor.authorMaia, André
dc.contributor.authorGuieu, Samuel
dc.contributor.authorSoares, Ana Raquel
dc.contributor.authorSantos, Clementina M.M.
dc.contributor.authorVieira, Sandra I.
dc.contributor.authorSilva, Artur
dc.date.accessioned2022-03-02T16:30:21Z
dc.date.available2022-03-02T16:30:21Z
dc.date.issued2022
dc.description.abstractReversing 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.pt_PT
dc.description.sponsorshipThanks 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).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAlbuquerque, 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. 1-6pt_PT
dc.identifier.doi10.1021/acsmedchemlett.1c00604pt_PT
dc.identifier.issn1948-5875
dc.identifier.urihttp://hdl.handle.net/10198/25132
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherACSpt_PT
dc.relationBPD/UI98/4861/2017pt_PT
dc.relationAssociated Laboratory for Green Chemistry - Clean Technologies and Processes
dc.relationInstitute for Biomedicine - Aveiro
dc.relationCICECO-Aveiro Institute of Materials
dc.relationIdentification of novel therapeutic targets to modulate proteostasis in humans
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectSteroid−quinoline hybridspt_PT
dc.subjectProtein aggregationpt_PT
dc.subjectAmyloid-β (Aβ) peptidept_PT
dc.subjectProtein misfolding diseasespt_PT
dc.titleSteroid–quinoline hybrids for disruption and reversion of protein aggregation processespt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleAssociated Laboratory for Green Chemistry - Clean Technologies and Processes
oaire.awardTitleInstitute for Biomedicine - Aveiro
oaire.awardTitleCICECO-Aveiro Institute of Materials
oaire.awardTitleIdentification of novel therapeutic targets to modulate proteostasis in humans
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F50006%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FBIM%2F04501%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FCTM%2F50011%2F2019/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F135655%2F2018/PT
oaire.citation.titleACS Medicinal Chemistry Letterspt_PT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStream6817 - DCRRNI ID
person.familyNameSantos
person.givenNameClementina M.M.
person.identifier.ciencia-id9018-DB9C-C590
person.identifier.orcid0000-0003-4380-7990
person.identifier.scopus-author-id7201458663
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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