Evaluation of computationally designed peptides against TWEAK, a cytokine of the tumour necrosis factor ligand family

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• dc.contributor.author Badia Villanueva, Miriam
• dc.contributor.author Defaus, Sira
• dc.contributor.author Foj, Ruben
• dc.contributor.author Andreu Martínez, David
• dc.contributor.author Oliva Miguel, Baldomero
• dc.contributor.author Sierra, Angels
• dc.contributor.author Fernández Fuentes, Narcís
• dc.date.accessioned 2021-02-15T06:48:14Z
• dc.date.available 2021-02-15T06:48:14Z
• dc.date.issued 2021
• dc.description.abstract The tumour necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumour necrosis factor ligand family and has been shown to be overexpressed in tumoral cells together with the fibroblast growth factor-inducible 14 (Fn14) receptor. TWEAK-Fn14 interaction triggers a set of intracellular pathways responsible for tumour cell invasion and migration, as well as proliferation and angiogenesis. Hence, modulation of the TWEAK-Fn14 interaction is an important therapeutic goal. The targeting of protein-protein interactions by external agents, e.g., drugs, remains a substantial challenge. Given their intrinsic features, as well as recent advances that improve their pharmacological profiles, peptides have arisen as promising agents in this regard. Here, we report, by in silico structural design validated by cell-based and in vitro assays, the discovery of four peptides able to target TWEAK. Our results show that, when added to TWEAK-dependent cellular cultures, peptides cause a down-regulation of genes that are part of TWEAK-Fn14 signalling pathway. The direct, physical interaction between the peptides and TWEAK was further elucidated in an in vitro assay which confirmed that the bioactivity shown in cell-based assays was due to the targeting of TWEAK. The results presented here are framed within early pre-clinical drug development and therefore these peptide hits represent a starting point for the development of novel therapeutic agents. Our approach exemplifies the powerful combination of in silico and experimental efforts to quickly identify peptides with desirable traits.
• dc.description.sponsorship The authors received support from the Spanish Ministry of Science (MINECO) [RYC2015-17519, BIO2017-83591-R, BIO2014-57518R, BIO2017-85329-R, AGL2013-48923-C2 and AGL2017-89097-C2-R2], the ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER) [FIS-PI14/00336 and FIS-PI18/00916], the EU Action NADIR FP7-228394 and the Maria de Maeztu Program for Center of Excellence program (AEI CEX2018-000792-M.).
• dc.format.mimetype application/pdf
• dc.identifier.citation Badia-Villanueva M, Defaus S, Foj R, Andreu D, Oliva B, Sierra A, Fernandez-Fuentes N. Evaluation of computationally designed peptides against TWEAK, a cytokine of the tumour necrosis factor ligand family. Int J Mol Sci. 2021; 22(3):1066. DOI: 10.3390/ijms22031066
• dc.identifier.doi http://dx.doi.org/10.3390/ijms22031066
• dc.identifier.issn 1422-0067
• dc.identifier.uri http://hdl.handle.net/10230/46472
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Int J Mol Sci. 2021; 22(3):1066
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/228394
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/RYC2015-17519
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BIO2017-83591-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2014-57518-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BIO2017-85329-R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/AGL2013-48923-C2
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/AGL2017-89097-C2-R2
• dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword TWEAK
• dc.subject.keyword Expression microarrays
• dc.subject.keyword Orthosteric peptides
• dc.subject.keyword Peptide design
• dc.subject.keyword Protein-protein interactions
• dc.subject.keyword Surface plasmon resonance
• dc.title Evaluation of computationally designed peptides against TWEAK, a cytokine of the tumour necrosis factor ligand family
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion