An N-capping asparagine-lysine-proline (NKP) motif contributes to a hybrid flexible/stable multifunctional peptide scaffold

Structural diversity drives multiple biological activities and mechanisms of action in linear peptides. Here we describe an unusual N-capping asparagine-lysine-proline (NKP) motif that confers a hybrid multifunctional scaffold to a computationally designed peptide (PaDBS1R7). PaDBS1R7 has a shorter...

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Bibliographic Details
Published in:	Chemical science (Cambridge) Vol. 13; no. 32; pp. 941 - 9424
Main Authors:	Cardoso, Marlon H, Chan, Lai Y, Cndido, Elizabete S, Buccini, Danieli F, Rezende, Samilla B, Torres, Marcelo D. T, Oshiro, Karen G. N, Silva, Ítala C, Gonçalves, Sónia, Lu, Timothy K, Santos, Nuno C, de la Fuente-Nunez, Cesar, Craik, David J, Franco, Octávio L
Format:	Journal Article
Language:	English
Published:	England Royal Society of Chemistry 17-08-2022 The Royal Society of Chemistry
Subjects:	Anticancer properties Biodiversity Biological computing Capping Chemistry Coils Hydrogen bonds Lysine Macrophages Peptides Proline Pseudomonas aeruginosa Scaffolds Wound healing
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Summary:	Structural diversity drives multiple biological activities and mechanisms of action in linear peptides. Here we describe an unusual N-capping asparagine-lysine-proline (NKP) motif that confers a hybrid multifunctional scaffold to a computationally designed peptide (PaDBS1R7). PaDBS1R7 has a shorter α-helix segment than other computationally designed peptides of similar sequence but with key residue substitutions. Although this motif acts as an α-helix breaker in PaDBS1R7, the Asn5 presents exclusive N-capping effects, forming a belt to establish hydrogen bonds for an amphipathic α-helix stabilization. The combination of these different structural profiles was described as a coil/N-cap/α-helix scaffold, which was also observed in diverse computational peptide mutants. Biological studies revealed that all peptides displayed antibacterial activities. However, only PaDBS1R7 displayed anticancer properties, eradicated Pseudomonas aeruginosa biofilms, decreased bacterial counts by 100-1000-fold in vivo , reduced lipopolysaccharide-induced macrophages stress, and stimulated fibroblast migration for wound healing. This study extends our understanding of an N-capping NKP motif to engineering hybrid multifunctional peptide drug candidates with potent anti-infective and immunomodulatory properties. An unusual N-capping asparagine-lysine-proline (5NKP7) motif yields a coil/N-cap/α-helix multifunctional scaffold in a computer-made peptide selective for anionic surfaces and with anticancer, antibacterial, antibiofilm, anti-infective ( in vivo ), and immunomodulatory potential.
Bibliography:	and supplementary references. See https://doi.org/10.1039/d1sc06998e Electronic supplementary information (ESI) available: Tables S1-S12, Fig. S1-S17 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-6520 2041-6539
DOI:	10.1039/d1sc06998e