Probing Anti-inflammatory Properties Independent of NF-κB Through Conformational Constraint of Peptide-Based Interleukin-1 Receptor Biased Ligands

Frontiers in Chemistry
Azade GeranurimiWilliam D Lubell

Abstract

Interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) and is a key cytokine mediator of inflammasome activation. IL-1β signaling leads to parturition in preterm birth (PTB) and contributes to the retinal vaso-obliteration characteristic of oxygen-induced retinopathy (OIR) of premature infants. Therapeutics targeting IL-1β and IL-1R are approved to treat rheumatoid arthritis; however, all are large proteins with clinical limitations including immunosuppression, due in part to inhibition of NF-κB signaling, which is required for immuno-vigilance and cytoprotection. The all-D-amino acid peptide 1 (101.10, H-d-Arg-d-Tyr-d-Thr-d-Val-d-Glu-d-Leu-d-Ala-NH2) is an allosteric IL-1R modulator, which exhibits functional selectivity and conserves NF-κB signaling while inhibiting other IL-1-activated pathways. Peptide 1 has proven effective in experimental models of PTB and OIR. Seeking understanding of the structural requirements for the activity and biased signaling of 1, a panel of twelve derivatives was synthesized employing the various stereochemical isomers of α-amino-γ-lactam (Agl) and α-amino-β-hydroxy-γ-lactam (Hgl) residues to constrain the D-Thr-D-Val dipeptide residue. Using circular dichroism spectroscopy, the peptide confo...Continue Reading

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Citations

Feb 9, 2021·Cytokine & Growth Factor Reviews·Elizabeth PrairieSylvain Chemtob
Jul 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anh Minh Thao NguyenWilliam D Lubell
Apr 1, 2020·Organic Letters·Enaam MasriJörg Rademann

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Methods Mentioned

BETA
acylation
column chromatography
Assay
protein assay
circular dichroism

Software Mentioned

Fluoview
GraphPad Prism
Axiovision
ImageJ
FIJI
MosaiX

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