A Spectroscopic and Molecular Dynamics Study on the Aggregation Properties of a Lipopeptide Analogue of Liraglutide, a Therapeutic Peptide against Diabetes Type 2
-
Published:2023-11-11
Issue:22
Volume:28
Page:7536
-
ISSN:1420-3049
-
Container-title:Molecules
-
language:en
-
Short-container-title:Molecules
Author:
Giannetti Micaela1, Palleschi Antonio1ORCID, Ricciardi Beatrice1, Venanzi Mariano1ORCID
Affiliation:
1. Department of Chemical Science and Technologies, University of Rome Tor Vergata, Via della Ricerca Scientifica 1, 00133 Rome, Italy
Abstract
The pharmacokinetics of peptide drugs are strongly affected by their aggregation properties and the morphology of the nanostructures they form in their native state as well as in their therapeutic formulation. In this contribution, we analyze the aggregation properties of a Liraglutide analogue (LG18), a leading drug against diabetes type 2. LG18 is a lipopeptide characterized by the functionalization of a lysine residue (K26) with an 18C lipid chain. To this end, spectroscopic experiments, dynamic light scattering measurements, and molecular dynamics simulations were carried out, following the evolution of the aggregation process from the small LG18 clusters formed at sub-micromolar concentrations to the mesoscopic aggregates formed by aged micromolar solutions. The critical aggregation concentration of LG18 in water (pH = 8) was found to amount to 4.3 μM, as assessed by the pyrene fluorescence assay. MD simulations showed that the LG18 nanostructures are formed by tetramer building blocks that, at longer times, self-assemble to form micrometric supramolecular architectures.
Funder
European Union Horizon 2020 Research and Innovation Program
Subject
Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science
Reference27 articles.
1. Apostolopoulos, V., Bojarska, J., Chai, T.-T., Elnagdy, S., Kaczmarek, K., Matsoukas, J., New, R., Parang, K., Lopez, O.P., and Parhiz, H. (2021). A Global Review on Short Peptides: Frontiers and Perspectives. Molecules, 26. 2. Apostolopoulos, V., Bojarska, J., Chai, T.-T., Feehan, J., Kaczmarek, K., Matsoukas, J.M., Paredes Lopez, O., Saviano, M., Skwarczynski, M., and Smith-Carpenter, J. (2022). New Advances in Short Peptides: Looking Forward. Molecules, 27. 3. Therapeutic Peptides: Current Applications and Future Directions;Wang;Sig. Transduct. Target Ther.,2022 4. The Current Status of Peptide Drug Discovery: Back to the Future?;Henninot;J. Med. Chem.,2018 5. Materials for oral delivery of proteins and peptides;Brown;Nat. Rev. Mater.,2020
|
|