Sandín, DanielValle, JavierChaves-Arquero, BelénPrats-Ejarque, GuillemLarrosa, María NievesGonzález-López, Juan JoséJiménez, María ÁngelesBoix, EsterAndreu Martínez, DavidTorrent Burgas, Marc2022-01-252022-01-252021Sandín D, Valle J, Chaves-Arquero B, Prats-Ejarque G, Larrosa MN, González-López JJ, Jiménez MÁ, Boix E, Andreu D, Torrent M. Rationally modified antimicrobial peptides from the N-terminal domain of human RNase 3 show exceptional serum stability. J Med Chem. 2021;64(15):11472-82. DOI: 10.1021/acs.jmedchem.1c007950022-2623http://hdl.handle.net/10230/52306Multidrug resistance against conventional antibiotics poses an important threat to human health. In this context, antimicrobial peptides (AMPs) have been extensively studied for their antibacterial activity and promising results have been shown so far. However, AMPs tend to be rather vulnerable to protease degradation, which offsets their therapeutic appeal. Here, we demonstrate how replacing functional residues in the antimicrobial region of human RNase 3-also named eosinophil cationic protein-by non-natural amino acids increases stability in human serum. These changes were also shown to reduce the hemolytic effect of the peptides in general terms, whereas the antimicrobial activity was reasonably preserved. Digestion profiles enabled us to design new peptides with superior stability and lower toxicity that could become relevant candidates to reach clinical stages.application/pdfeng© 2021 American Chemical Society. This work is licensed under a Creative Commons Attribution 4.0 International Licenseinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1021/acs.jmedchem.1c00795info:eu-repo/semantics/openAccess