Interleukin-1 Receptor Modulation Using β-Substituted α-Amino-γ-Lactam Peptides From Solid-Phase Synthesis and Diversification

As a key cytokine mediator of inflammation, interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) and activates various downstream signaling mediators, including NF-κB, which is required for immune vigilance and cellular protection. Toward the development of IL-1-targeting therapeutics which exhibit functional selectivity, the all-D-amino acid peptide 1 (101.10, H-D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala-NH 2 ) was conceived as an allosteric IL-1R modulator that conserves NF-κB signaling while inhibiting other IL-1-activated pathways. Employing β-hydroxy-α-amino-γ-lactam (Hgl) stereoisomers to study the conformation about the Thr 3 residue in 1 , [(3 R ,4 S )-Hgl 3 ]- 1 ( 2b ), among all possible diastereomers, was found to exhibit identical in vitro and in vivo activity as the parent peptide and superior activity to the α-amino-γ-lactam (Agl) counterpart. Noting the relevance of the β-hydroxyl substituent and configuration for the activity of (3 R ,4 S )- 2b , fifteen different β-substituted-Agl 3 analogs of 1 (e.g., 2c-q ) have now been synthesized by a combination of solution- and solid-phase methods employing N -Fmoc-β-substituted-Agl 3 -Val-OH dipeptide building blocks. Introduction of a β-azido-Agl 3 residue into the resin bound peptide and subsequent reduction and CuAAC chemistry gave access to a series of amine and triazole derivatives (e.g., 2h-q ). β-Substituted-[Agl 3 ]- 1 analogs 2c-q exhibited generally similar circular dichroism (CD) spectra as that of Hgl analog 2b in water, presenting curve shapes indicative of β-turn structures. The relevance of the β-substituent was indicated in rodent models of preterm labor and retinopathy of prematurity (ROP), in which certain analogs inhibited preterm birth and vaso-obliteration, respectively, with activity similar to 1 and 2b . The β-substituted-[Agl 3 ]- 1 analogs exhibited functional selectivity on IL-1-induced signaling pathways. The described solid-phase method has provided discerning probes for exploring peptide structure-activity relationships and valuable leads for developing prototypes to treat inflammatory events leading to prematurity and retinopathy of prematurity, which are leading causes of infant morbidity and blindness respectively.

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