Pioneering anti-inflammatory therapy: The path to precision therapy with C3aR peptide libraries

Abstract. Inflammation, a pervasive process with profound implications for tissue, joint, and vascular health, underscores the critical importance of immune system regulation in maintaining bodily homeostasis. Central to this regulatory network is the complement system, a complex array of proteins that orchestrate immune responses to infections and cellular damage. Among these proteins, the complement component 3a receptor (C3aR) serves as a pivotal mediator, triggering inflammatory cascades upon binding to the anaphylatoxin C3a. Targeting C3aR has emerged as a promising strategy for anti-inflammatory therapy, driven by recent advances in structural biology elucidating the complex architecture of the C3a-C3aR interaction. This study focuses on the design of high-affinity peptides targeting the C3aR receptor, leveraging ligand design and docking techniques to optimize binding interactions. Utilizing computational tools with sophisticated algorithms, we modeled the binding affinity of mutated ligands with the C3aR receptor, providing insights into the potential efficacy of peptide-based therapeutics. Our findings reveal that mutations at residues G74 and A76 enhance the binding affinity of the ligand with the C3aR receptor, offering a promising avenue for the development of novel anti-inflammatory agents. By elucidating the molecular determinants underlying peptide-receptor interactions within the C3a system, this study advances our understanding of inflammation biology and lays the groundwork for the rational design of targeted therapeutics. These insights hold potential for the development of potent and selective C3aR agonists/antagonists, offering new avenues for the treatment of inflammatory diseases and enhancing patient outcomes.