Design and antimicrobial activities of <scp>LL</scp>‐37 derivatives inhibiting the formation of <i>Streptococcus mutans</i> biofilm

Zhao, Chen; Yang, Guang; Lu, Shengsheng; Chen, Daiwei; Fan, Sheng Di; Xu, Junyang; Wu, Buling; He, Jian

doi:10.1111/cbdd.13419

Cited by 29 publications

(20 citation statements)

References 34 publications

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“…Several studies have characterized various fragments of LL-37 primarily for their antimicrobial activity (Kanthawong et al, 2012) but also for their antibiofilm, antiviral, spermicidal, and immunomodulatory functions (Tripathi et al, 2015). These examples of synthetic cathelicidin-derived peptides do not even begin to scratch the surface of the many studies that manipulate the amino acid sequence of LL-37 and various peptide fragments to rationally design derivatives with enhanced biological activities (e.g., Chen et al, 2019).…”

Section: Synthetic Hdps and Clinical Applicationsmentioning

confidence: 99%

Cathelicidin Host Defense Peptides and Inflammatory Signaling: Striking a Balance

et al. 2020

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Host-defense peptides (HDPs) are vital components of innate immunity in all vertebrates. While their antibacterial activity toward bacterial cells was the original focus for research, their ability to modulate immune and inflammatory processes has emerged as one of their major functions in the host and as a promising approach from which to develop novel therapeutics targeting inflammation and innate immunity. In this review, with particular emphasis on the cathelicidin family of peptides, the roles of natural HDPs are examined in managing immune activation, cellular recruitment, cytokine responses, and inflammation in response to infection, as well as their contribution(s) to various inflammatory disorders and autoimmune diseases. Furthermore, we discuss current efforts to develop synthetic HDPs as therapeutics aimed at restoring balance to immune responses that are dysregulated and contribute to disease pathologies.

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Section: Synthetic Hdps and Clinical Applicationsmentioning

confidence: 99%

Cathelicidin Host Defense Peptides and Inflammatory Signaling: Striking a Balance

et al. 2020

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“…Both PSMα3 and hLL-37 are cleaved in vivo into active truncations with diverse activities [32][33][34][35][36] . Some hLL-37 fragments show a diverse array of selectivity against microbial strains, and additional functions within the immune system 34,37,38 . Bacterial proteases can too cleave LL-37, supposedly for degradation or to release virulence factors 36 .…”

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confidence: 99%

The Human LL-37(17-29) antimicrobial peptide reveals a functional supramolecular structure

2020

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Here, we demonstrate the self-assembly of the antimicrobial human LL-37 active core (residues 17-29) into a protein fibril of densely packed helices. The surface of the fibril encompasses alternating hydrophobic and positively charged zigzagged belts, which likely underlie interactions with and subsequent disruption of negatively charged lipid bilayers, such as bacterial membranes. LL-37 17-29 correspondingly forms wide, ribbon-like, thermostable fibrils in solution, which co-localize with bacterial cells. Structure-guided mutagenesis analyses supports the role of self-assembly in antibacterial activity. LL-37 17-29 resembles, in sequence and in the ability to form amphipathic helical fibrils, the bacterial cytotoxic PSMα3 peptide that assembles into cross-α amyloid fibrils. This argues helical, self-assembling, basic building blocks across kingdoms of life and points to potential structural mimicry mechanisms. The findings expose a protein fibril which performs a biological activity, and offer a scaffold for functional and durable biomaterials for a wide range of medical and technological applications.

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“…Human LL-37 (hLL-37) AMP, a hCAP-18 protein cleavage product, is also known to form fibrils (20). LL-37 is expressed by various mammalian cells and is considered to play an important role in the first line of defense against pathogens (21)(22)(23)(24)(25)(26). Fibrillation of LL-37 was found critical for binding DNA and affecting receptors in the immune system (27).…”

mentioning

confidence: 99%

“…S1) and are cleaved in-vivo into active derivatives (36)(37)(38)(39)(40)(41)(42). Many hLL-37 derivatives show a diverse array of selectivity against microbial strains, and additional functions within the immune system (26,36,37,43,44).…”

mentioning

confidence: 99%

The Human LL-37(17-29) Antimicrobial Peptide Reveals a Functional Supramolecular Nanostructure

Engelberg

Landau

2020

Preprint

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Here we demonstrate, by crystal structures, the self-assembly of the human and primate antibacterial LL-37 active core (residues 17-29) into a densely packed hexameric fibrillar architecture of amphipathic helices. The fibril is composed of four-helix bundles with a hydrophobic core, while a network of polar interactions stabilizes contacts between bundles, overall forming a stable fibrillar configuration that is also thermostable in solution. Despite similarity in sequence and the formation of fibrils composed of amphipathic helices, the LL-3717-29 fibril structure was significantly different from the cytotoxic bacterial PSMα3 peptide, which fibrillates into amyloid cross-α fibrils. LL-3717-29 formed wide, ribbon-like fibrils, which colocalized with bacterial cells; structure-guided mutagenesis analysis indicated the importance of its helical self-assembly in antibacterial activity and interactions with bacteria. This work extends the previously reported link between antibacterial activity and the formation of ordered amyloid fibrils, to helical, stable, hexameric fibrils. This fibril-antibacterial link suggests a tunable mechanism of action and offers a prospective to design antimicrobial peptides with improved stability and bioavailability.

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Design and antimicrobial activities of LL‐37 derivatives inhibiting the formation of Streptococcus mutans biofilm

Cited by 29 publications

References 34 publications

Cathelicidin Host Defense Peptides and Inflammatory Signaling: Striking a Balance

Cathelicidin Host Defense Peptides and Inflammatory Signaling: Striking a Balance

The Human LL-37(17-29) antimicrobial peptide reveals a functional supramolecular structure

The Human LL-37(17-29) Antimicrobial Peptide Reveals a Functional Supramolecular Nanostructure

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