Aggregation properties of a therapeutic peptide for rheumatoid arthritis: A spectroscopic and molecular dynamics study

Abstract The biological properties of therapeutic peptides, such as their pharmacokinetics and pharmacodynamics, are correlated with their structure and aggregation properties. Herein, we studied the aggregation properties of a therapeutic peptide (CIGB-814), currently in phase 2 clinical trial, for the treatment of rheumatoid arthritis over a wide range of concentrations (µM–mM). We applied spectroscopic techniques (fluorescence, circular dichroism, resonance, and dynamic light scattering), atomic force microscopy, and molecular dynamics simulations to determine the aggregation mechanism of CIGB-814. We found that the hierarchical aggregation of CIGB-814 at micromolar concentrations was initiated by the formation of peptide oligomers. Subsequently, the peptide oligomers trigger the nucleation and growth of peptide nanostructures (cac = 123 µM), ultimately leading to the fibrillization of CIGB-814 (cac’ = 508 µM). These results pave the way for a deeper understanding of the CIGB-814 therapeutic activity and may give important insights on its pharmacokinetics.