Details

Autor(en) / Beteiligte

• Todorović, Viktor
• Su, Zhi
• Putman, C Brent
• Kakavas, Stevan J
• Salte, Katherine M
• McDonald, Heath A
• Wetter, Joseph B
• Paulsboe, Stephanie E
• Sun, Qi
• Gerstein, Clare E
• Medina, Limary
• Sielaff, Bernhard
• Sadhukhan, Ramkrishna
• Stockmann, Henning
• Richardson, Paul L
• Qiu, Wei
• Argiriadi, Maria A
• Henry, Rodger F
• Herold, J Martin
• Shotwell, J Brad
• McGaraughty, Steve P
• Honore, Prisca
• Gopalakrishnan, Sujatha M
• Sun, Chaohong C
• Scott, Victoria E

Titel

Small Molecule IL-36γ Antagonist as a Novel Therapeutic Approach for Plaque Psoriasis

Ist Teil von

• Scientific reports, 2019-06, Vol.9 (1), p.9089-15, Article 9089

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2019

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• IL-36 cytokines are pro-inflammatory members of the IL-1 family that are upregulated in inflammatory disorders. Specifically, IL-36γ is highly expressed in active psoriatic lesions and can drive pro-inflammatory processes in 3D human skin equivalents supporting a role for this target in skin inflammation. Small molecule antagonists of interleukins have been historically challenging to generate. Nevertheless, we performed a small molecule high-throughput screen to identify IL-36 antagonists using a novel TR-FRET binding assay. Several compounds, including 2-oxypyrimidine containing structural analogs of the marketed endothelin receptor A antagonist Ambrisentan, were identified as hits from the screen. A-552 was identified as a the most potent antagonist of human IL-36γ, but not the closely related family member IL-36α, was capable of attenuating IL-36γ induced responses in mouse and human disease models. Additionally, x-ray crystallography studies identified key amino acid residues in the binding pocket present in human IL-36γ that are absent in human IL-36α. A-552 represents a first-in-class small molecule antagonist of IL-36 signaling that could be used as a chemical tool to further investigate the role of this pathway in inflammatory skin diseases such as psoriasis.