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Discovery of novel immunopharmacological ligands targeting the IL-17 inflammatory pathway.

Abstract：

:Interleukin 17 (IL-17) is a proinflammatory cytokine that acts as an immune checkpoint for several autoimmune diseases. Therapeutic neutralizing antibodies that target this cytokine have demonstrated clinical efficacy in psoriasis. However, biologics have limitations such as their high cost and their lack of oral bioavailability. Thus, it is necessary to expand the therapeutic options for this IL-17A/IL-17RA pathway, applying novel drug discovery methods to find effective small molecules. In this work, we combined biophysical and cell-based assays with structure-based docking to find novel ligands that target this pathway. First, a virtual screening of our chemical library of 60000 compounds was used to identify 67 potential ligands of IL-17A and IL-17RA. We developed a biophysical label-free binding assay to determine interactions with the extracellular domain of IL-17RA. Two molecules (CBG040591 and CBG060392) with quinazolinone and pyrrolidinedione chemical scaffolds, respectively, were confirmed as ligands of IL-17RA with micromolar affinity. The anti-inflammatory activity of these ligands as cytokine-release inhibitors was evaluated in human keratinocytes. Both ligands inhibited the release of chemokines mediated by IL-17A, with an IC50 of 20.9 ± 12.6 μM and 23.6 ± 11.8 μM for CCL20 and an IC50 of 26.7 ± 13.1 μM and 45.3 ± 13.0 μM for CXCL8. Hence, they blocked IL-17A proinflammatory activity, which is consistent with the inhibition of the signalling of the IL-17A receptor by ligand CBG060392. Therefore, we identified two novel immunopharmacological ligands targeting the IL-17A/IL-17RA pathway with antiinflammatory efficacy that can be promising tools for a drug discovery program for psoriasis.

journal_name

Int Immunopharmacol

journal_title

International immunopharmacology

authors

Álvarez-Coiradas E,Munteanu CR,Díaz-Sáez L,Pazos A,Huber KVM,Loza MI,Domínguez E

doi

10.1016/j.intimp.2020.107026

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

107026

issue

Pt A

eissn

1567-5769

issn

1878-1705

pii

S1567-5769(20)31830-0

journal_volume

89

pub_type

杂志文章

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