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

Area of Science:

• Medicinal Chemistry
• Immunology
• Peptide Therapeutics

Background:

• Interleukin-1β (IL-1β) is a key inflammatory cytokine mediating cellular responses via the IL-1 receptor (IL-1R).
• Targeting IL-1R is crucial for treating inflammatory diseases, but achieving functional selectivity remains a challenge.
• NF-κB signaling, activated by IL-1R, is vital for immune defense and cellular protection.

Purpose of the Study:

• To develop IL-1R-targeting therapeutics with functional selectivity, conserving NF-κB signaling while inhibiting other IL-1-activated pathways.
• To explore structure-activity relationships of all-D-amino acid peptide 1 and its analogs, focusing on modifications at the Thr3 residue.

Main Methods:

• Synthesis of β-hydroxy-α-amino-γ-lactam (Hgl) and β-substituted-α-amino-γ-lactam (Agl) stereoisomers and analogs of peptide 1.
• Utilized solution- and solid-phase peptide synthesis techniques, including Fmoc chemistry and copper-catalyzed azide-alkyne cycloaddition (CuAAC).
• Assessed peptide activity in vitro and in vivo, including rodent models of preterm labor and retinopathy of prematurity (ROP), and analyzed circular dichroism (CD) spectra.

Main Results:

• The Hgl analog [(3R,4S)-Hgl3]-1 (2b) showed comparable in vitro and in vivo activity to peptide 1 and superior activity to its Agl counterpart.
• Fifteen β-substituted-Agl3 analogs of peptide 1 were synthesized, with certain analogs demonstrating efficacy in inhibiting preterm birth and ROP-related vaso-obliteration.
• Circular dichroism spectra indicated that the β-substituted-Agl3 analogs adopt β-turn structures, similar to the Hgl analog 2b.

Conclusions:

• The β-substituent and its configuration are critical for the activity of IL-1R modulators.
• The developed β-substituted-[Agl3]-1 analogs exhibit functional selectivity on IL-1-induced signaling pathways.
• These findings provide valuable leads for developing therapeutic prototypes to treat inflammatory conditions contributing to infant morbidity and blindness.