Aggregation properties of a therapeutic peptide for rheumatoid arthritis: A spectroscopic and molecular dynamics study
Rita Cimino,
Marco Savioli,
Noemi Ferrante Carrante,
Ernesto Placidi,
Hilda Garay-Perez,
Matilde López-Abad,
Alexis Musacchio Lasa,
Maria Del Carmen Domínguez-Horta,
Emanuela Gatto,
Francesca Cavalieri,
Gianfranco Bocchinfuso,
Mariano Venanzi
Affiliations
Rita Cimino
PEPSA-LAB, Department of Chemical Sciences and Technology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy
Marco Savioli
PEPSA-LAB, Department of Chemical Sciences and Technology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy
Noemi Ferrante Carrante
PEPSA-LAB, Department of Chemical Sciences and Technology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy
Ernesto Placidi
Department of Physics, University of Rome ‘Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
Hilda Garay-Perez
Centre for Genetic Engineering and Biotechnology, PO Box 6162, 10600, Havana, Cuba
Matilde López-Abad
Centre for Genetic Engineering and Biotechnology, PO Box 6162, 10600, Havana, Cuba
Alexis Musacchio Lasa
Centre for Genetic Engineering and Biotechnology, PO Box 6162, 10600, Havana, Cuba
Maria Del Carmen Domínguez-Horta
Centre for Genetic Engineering and Biotechnology, PO Box 6162, 10600, Havana, Cuba
Emanuela Gatto
PEPSA-LAB, Department of Chemical Sciences and Technology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy
Francesca Cavalieri
PEPSA-LAB, Department of Chemical Sciences and Technology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy; School of Science, RMIT University, Melbourne, VIC 3001, Australia; Corresponding author.
Gianfranco Bocchinfuso
PEPSA-LAB, Department of Chemical Sciences and Technology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy
Mariano Venanzi
PEPSA-LAB, Department of Chemical Sciences and Technology, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133, Rome, Italy; Corresponding author.
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.
