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Open AccessArticle

Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity

1
Department of Microbiology, Faculty of Biochemistry, Biophysics and Biotechnology of Jagiellonian University, 30-387 Krakow, Poland
2
Malopolska Center of Biotechnology, Jagiellonian University, 30-387 Krakow, Poland
3
Biotechnology Core Facility Branch, Division of Scientific Resources, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA
4
Department of Oral Immunity and Infectious Diseases, University of Louisville School of Dentistry, University of Louisville, Louisville, KY 40202, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(23), 9126; https://doi.org/10.3390/ijms21239126
Received: 14 November 2020 / Revised: 26 November 2020 / Accepted: 27 November 2020 / Published: 30 November 2020
(This article belongs to the Special Issue Peptides for Health Benefits 2020)
LL-37, the only member of the mammalian cathelicidin in humans, plays an essential role in innate immunity by killing pathogens and regulating the inflammatory response. However, at an inflammatory focus, arginine residues in LL-37 can be converted to citrulline via a reaction catalyzed by peptidyl-arginine deiminases (PAD2 and PAD4), which are expressed in neutrophils and are highly active during the formation of neutrophil extracellular traps (NETs). Citrullination impairs the bactericidal activity of LL-37 and abrogates its immunomodulatory functions. Therefore, we hypothesized that citrullination-resistant LL-37 variants would retain the functionality of the native peptide in the presence of PADs. To test this hypothesis, we synthetized LL-37 in which arginine residues were substituted by homoarginine (hArg-LL-37). Bactericidal activity of hArg-LL-37 was comparable with that of native LL-37, but neither treatment with PAD4 nor exposure to NETs affected the antibacterial and immunomodulatory activities of hArg-LL-37. Importantly, the susceptibilities of LL-37 and hArg-LL-37 to degradation by proteases did not significantly differ. Collectively, we demonstrated that citrullination-resistant hArg-LL-37 is an attractive lead compound for the generation of new agents to treat bacterial infections and other inflammatory diseases associated with enhanced PAD activity. Moreover, our results provide a proof-of-concept for synthesis of therapeutic peptides using homoarginine. View Full-Text
Keywords: LL-37; arginine; homoarginine; citrullination; NETs LL-37; arginine; homoarginine; citrullination; NETs
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MDPI and ACS Style

Bryzek, D.; Golda, A.; Budziaszek, J.; Kowalczyk, D.; Wong, A.; Bielecka, E.; Shakamuri, P.; Svoboda, P.; Pohl, J.; Potempa, J.; Koziel, J. Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity. Int. J. Mol. Sci. 2020, 21, 9126. https://doi.org/10.3390/ijms21239126

AMA Style

Bryzek D, Golda A, Budziaszek J, Kowalczyk D, Wong A, Bielecka E, Shakamuri P, Svoboda P, Pohl J, Potempa J, Koziel J. Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity. International Journal of Molecular Sciences. 2020; 21(23):9126. https://doi.org/10.3390/ijms21239126

Chicago/Turabian Style

Bryzek, Danuta; Golda, Anna; Budziaszek, Joanna; Kowalczyk, Dominik; Wong, Alicia; Bielecka, Ewa; Shakamuri, Priyanka; Svoboda, Pavel; Pohl, Jan; Potempa, Jan; Koziel, Joanna. 2020. "Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity" Int. J. Mol. Sci. 21, no. 23: 9126. https://doi.org/10.3390/ijms21239126

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