Interleukin-1 Receptor Modulation Using ?-Substituted ?-Amino-?-Lactam Peptides From Solid-Phase Synthesis and Diversification.

ABSTRACT: As a key cytokine mediator of inflammation, interleukin-1? (IL-1?) binds to the IL-1 receptor (IL-1R) and activates various downstream signaling mediators, including NF-?B, 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-NH₂) was conceived as an allosteric IL-1R modulator that conserves NF-?B signaling while inhibiting other IL-1-activated pathways. Employing ?-hydroxy-?-amino-?-lactam (Hgl) stereoisomers to study the conformation about the Thr³ residue in 1, [(3R,4S)-Hgl³]-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 ?-amino-?-lactam (Agl) counterpart. Noting the relevance of the ?-hydroxyl substituent and configuration for the activity of (3R,4S)-2b, fifteen different ?-substituted-Agl³ analogs of 1 (e.g., 2c-q) have now been synthesized by a combination of solution- and solid-phase methods employing N-Fmoc-?-substituted-Agl³-Val-OH dipeptide building blocks. Introduction of a ?-azido-Agl³ 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). ?-Substituted-[Agl³]-1 analogs 2c-q exhibited generally similar circular dichroism (CD) spectra as that of Hgl analog 2b in water, presenting curve shapes indicative of ?-turn structures. The relevance of the ?-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 ?-substituted-[Agl³]-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.

SUBMITTER: Geranurimi A 

PROVIDER: S-EPMC7783595 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature