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

Marlon H. Cardoso; Lai Y. Chan; Elizabete S. Cândido; Danieli F. Buccini; Samilla B. Rezende; Marcelo D. T. Torres; Karen G. N. Oshiro; Ítala C. Silva; Sónia Gonçalves; Timothy K. Lu; Nuno C. Santos; Cesar de la Fuente-Nunez; David J. Craik; Octávio L. Franco

doi:10.1039/D1SC06998E

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

Marlon H. Cardoso,

*^abcd Lai Y. Chan,

^e Elizabete S. Cândido,^ab Danieli F. Buccini,^a Samilla B. Rezende,

^a Marcelo D. T. Torres,

^f Karen G. N. Oshiro,

^ac Ítala C. Silva,

^g Sónia Gonçalves,^g Timothy K. Lu,^h Nuno C. Santos,

^g Cesar de la Fuente-Nunez,

^f David J. Craik

*^e and Octávio L. Franco

*^abc

Author affiliations

* Corresponding authors

^a S-Inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco Avenida Tamandaré 6000, Campo Grande – MS, Brazil
E-mail: marlonhenrique6@gmail.com, d.craik@imb.uq.edu.au, ocfranco@gmail.com

^b Centro de Análises Proteômicas e Bioquímicas, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, SGAN 916 Módulo B, Asa Norte, Brasília – DF, Brazil

^c Programa de Pós-Graduação em Patologia Molecular, Faculdade de Medicina, Universidade de Brasília, Campus Darcy Ribeiro, Asa Norte, Brasília – DF, Brazil

^d Instituto de Biociências (INBIO), Universidade Federal de Mato Grosso do Sul, Cidade Universitária, Campo Grande, Mato Grosso do Sul, Brazil

^e Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Australia

^f Machine Biology Group, Departments of Psychiatry and Microbiology, Institute for Biomedical Informatics, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, Departments of Bioengineering and Chemical and Biomolecular Engineering, School of Engineering and Applied Science, Penn Institute for Computational Science, University of Pennsylvania, Philadelphia, Pennsylvania, USA

^g Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

^h Synthetic Biology Group, MIT Synthetic Biology Center, The Center for Microbiome Informatics and Therapeutics, Research Laboratory of Electronics, Department of Biological Engineering, Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge – MA, USA

Abstract

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.

Chemical Science

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

Abstract

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

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