Evaluation of Computationally Designed Peptides against TWEAK, a Cytokine of the Tumour Necrosis Factor Ligand Family.
TWEAK
expression microarrays
orthosteric peptides
peptide design
protein-protein interactions
surface plasmon resonance
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
21 Jan 2021
21 Jan 2021
Historique:
received:
23
11
2020
revised:
12
01
2021
accepted:
15
01
2021
entrez:
26
1
2021
pubmed:
27
1
2021
medline:
7
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 33494438
pii: ijms22031066
doi: 10.3390/ijms22031066
pmc: PMC7866087
pii:
doi:
Substances chimiques
Cytokine TWEAK
0
Peptides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministerio de Economía y Competitividad
ID : RYC2015-17519, BIO2017-83591-R, BIO2014-57518R, BIO2017-85329-R, AGL2013-48923-C2 and AGL2017-89097-C2-R2
Organisme : ISCIII - Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER)
ID : FIS-PI14/00336 and FIS-PI18/00916
Organisme : EU Action
ID : NADIR FP7-228394
Organisme : Maria de Maeztu Program for Center of Excellence program
ID : AEI CEX2018-000792-M
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