A key cytokine mediator of inflammation, interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) activating various downstream signaling mediators. Current therapy for regulating IL-1R-mediated pathology employ proteins which block non-selectively all signals triggered by the native orthosteric ligand IL-1β. To develop anti-IL-1 therapeutics which diminish inflammation without compromising immuno-vigilance, the all-D-amino acid peptide 101.10 (H-D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala-NH₂) was conceived as an allosteric IL-1R modulator that conserves NF-kB signaling while inhibiting other IL-1-activated pathways. Employing α-amino-γ-lactam (Agl) and β-hydroxy-α-amino-γ-lactam (Hgl) stereoisomers to study the conformation about the D-Thr³ residue of 101.10, analogs were synthesized exhibiting discrete circular dichroism spectra and functional selectivity in different biological pathways [1]. In models of preterm birth and retinopathy of prematurity, this series demonstrated the relevance of inhibition of specific kinase pathways for delaying labor and diminishing vaso-obliteration. Notably, [(3R,4S)-Hgl³]-101.10 exhibited a β-turn conformation and similar efficacy as 101.10. In the interest to study further side chain restriction in constrained peptides, β-substituted Agl residues have also been prepared using Mitsunobu chemistry and sulfamidate nucleophilic ring opening to provide constrained mimics of a variety of amino acids [2].  The utility of this peptide-based approach for regulating inflammation will be presented.

1. Geranurimi, A.; Cheng, C. W. H.; Quiniou, C.; Hou, X.; Zhu, T.; Rivera, J. C.; St-Cyr, D.; Beauregard, K.; Bernard-Gauthier, V.; Chemtob, S.; Lubell, W. D. Frontiers Chem., 2019, 7, 23.
2. 1. Geranurimi, A.; Lubell, W. D. Org. Lett., 2018, 20, 6126-6129.