What can we learn about functional importance of human antimicrobial peptide LL-37 in the oral environment from severe congenital neutropenia (Kostmann disease)?

Nilsson, Bengt‐Olof

doi:10.1016/j.peptides.2020.170311

Cited by 11 publications

(7 citation statements)

References 45 publications

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“…The human peptide LL-37 produced by neutrophils and epithelial cells had an inhibitory effect on Gram-positive and Gram-negative bacteria (Nilsson, 2020), and also played an important role in wound healing (Ramos et al, 2011), angiogenesis, and arteriogenesis (Koczulla et al, 2003). Peptide LvHemB1 induced apoptosis by permeating cells and targeting mitochondrial voltage-dependent anion channel 1 (VDAC1); thus, it could be used as an anticancer agent for the treatment of human cervical (HeLa), oesophageal (EC109), hepatocellular (HepG2), and bladder (EJ) cancer cell lines (Liu et al, 2022).…”

Section: Applications In Medicinementioning

confidence: 99%

Antimicrobial peptides: Design, chemical synthesis, activity evaluation, and application

Yang,

Wang,

et al. 2023

IFRJ

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Antimicrobial peptides (AMPs) are active short peptides that exist in microorganisms, insects, amphibians, plants, and mammals. Some naturally occurring AMPs have low antimicrobial activity, high haemolysis, potential toxicity toward mammalian cells, and high susceptibility to proteolytic degradation, which limit their practical application. In recent years, many efforts have been made to design and modify AMPs to improve their properties. The present review focuses on site-directed mutation, truncation, hybridisation, capping, and cyclisation of AMPs. The review further introduces the application of solid-phase peptide synthesis technology for AMPs, and summarises the methods for evaluating the antimicrobial activity of AMPs. The in-depth research on AMPs is expected to play an essential role in the fields of agriculture, animal husbandry, food industry, and medicine.

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Section: Applications In Medicinementioning

confidence: 99%

Antimicrobial peptides: Design, chemical synthesis, activity evaluation, and application

Yang,

Wang,

et al. 2023

IFRJ

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“…Figure 2B shows dose-dependent cytotoxicity of LL18, with a calculated IC 50 of 38.5 ± 0.2 μM (Figure S2C). LL18 may thus provide a safer (and cheaper) alternative to LL37, which was shown to be cytotoxic for different human cell types at concentrations ranging from 2 μM to 13 μM, 47 with an IC 50 of 5 μM for osteoblasts in particular. 48 Given that bone is a highly vascularized tissue, cellular toxicity of HG dil and LL18 were also analyzed using dog RBCs (Figure 3).…”

Section: Cytotoxicity and Hemolysismentioning

confidence: 99%

“…In a second experiment (Figure 5B), LL18 at 300 μM (C3) was tested in combination with different low VH concentrations: 10; Although cytotoxicity and hemolytic effects were observed at much lower concentrations in vitro, 47,53,54 no safety concerns regarding local or systemic adverse events were detected for up to 712 μM of LL37 topically applied in patients chronic leg ulcers. 78 Thus, we assumed that intralesional administration of up to 429 μM of the less cytotoxic LL18 into bone defects could be safely applied, to examine the balance between antimicrobial efficacy and tissue damage.…”

Section: Osteomyelitis Model and Bacterial Loadmentioning

confidence: 99%

Injectable hydrogel as a carrier of vancomycin and a cathelicidin‐derived peptide for osteomyelitis treatment

Sobrinho

Pereira

Silva

et al. 2022

J Biomedical Materials Res

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A local drug delivery system that attempts to find a suitable balance between antimicrobial and regenerative actions was developed for osteomyelitis treatment (OM). This system combines the angiogenic and immunomodulatory peptide LLKKK18 (LL18) and vancomycin hydrochloride (VH), loaded into an injectable oxidized dextrin (ODEX)‐based hydrogel (HG). In vitro cytotoxicity was analyzed in MC3T3‐E1 pre‐osteoblasts and erythrocytes. The kinetics of LL18 release was studied. Antimicrobial activity was assessed in vitro against a clinical Methicillin‐Resistant Staphylococcus aureus (MRSA) strain. A rat model of acute OM was developed by direct inoculation into a tibia defect, concomitantly with the implantation of the drug‐loaded HG. The local bioburden was quantified and damage in surrounding tissues was examined histologically. In vitro, ODEX‐based HG displayed a safe hemolytic profile. Half of LL18 (53%) is released during the swelling phase at physiological pH, then being gradually released until complete HG degradation. LL18‐loaded HG at 300 μM was the most effective peptide formulation in decreasing in vivo infection among concentrations ranging from 86 to 429 μM. The histopathological scores observed in vivo varied with the LL18 concentration in a dose‐dependent manner. VH at 28 mM completely eradicated bacteria, although with substantial tissue injury. We have found that sub‐millimolar doses of VH combined with LL18 at 300 μM may suffice to eradicate the infection, with reduced tissue damage. We propose an easy‐to‐handle, shape‐fitting HG formulation with the potential to treat MRSA‐infected bone with low VH doses associated with LL18.

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“…Recent studies have also indicated that AMPs can have important immunomodulatory mediators with diverse activities. , These properties have been associated with a couple of physiological processes such as reduction of proinflammatory cytokine levels, modulation of chemokine expression, stimulation of angiogenesis, enhanced wound healing, or leukocyte activation . Furthermore, their deficiency or enhanced expression can play crucial roles in autoimmune disorders as well as in the progression of cancer, respiratory diseases, or skin diseases. ,− Majority of their broad antimicrobial and immunomodulatory properties rely on their capability to interact with various sets of biomacromolecules. Besides their most well-known interactions with lipids of the cell membranes, there are several examples of peptide interactions with macromolecules, covering DNA, , proteins, − or glycosaminoglycans .…”

Section: Introductionmentioning

confidence: 99%

Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System

et al. 2021

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Owing to their potential applicability against multidrug-resistant bacteria, antimicrobial peptides (AMPs) or host defense peptides (HDPs) gain increased attention. Besides diverse immunomodulatory roles, their classical mechanism of action mostly involves membrane disruption of microbes. Notably, their unbalanced overexpression has also been associated with host cell cytotoxicity in various diseases. Relatedly, AMPs can be subject to aggregate formation, either via self-assembly or together with other compounds, which has demonstrated a modulation effect on their biological functions, thus highly relevant both for drug targeting projects and understanding their in vivo actions. However, the molecular aspects of the related assembly formation are not understood. Here, we focused in detail on an experimentally studied AMP−drug system, i.e., CM15−suramin, and performed all-atom and coarse-grain (CG) simulations. Results obtained for all systems were in close line with experimental observations and indicate that the CM15−suramin aggregation is an energetically favorable and dynamic process. In the presence of bilayers, the peptide−drug assembly formation was highly dependent on lipid composition, and peptide aggregates themselves were also capable of binding to the membranes. Interestingly, longer CG simulations with zwitterionic membranes indicated an intermediate state in the presence of both AMP−drug assemblies and monomeric peptides located on the membrane surface. In sharp contrast, larger AMP−drug aggregates could not be detected with a negatively charged membrane, rather the AMPs penetrated its surface in a monomeric form, in line with previous in vitro observations. Considering experimental and theoretical results, it is promoted that in biological systems, cationic AMPs may often form associates with anionic compounds in a reversible manner, resulting in lower bioactivity. This is only mildly affected by zwitterionic membranes; however, membranes with a negative charge strongly alter the energetic preference of AMP assemblies, resulting in the dissolution of the complexes into the membrane. The phenomenon observed here at a molecular level can be followed in several experimental systems studied recently, where peptides interact with food colors, drug molecules, or endogenous compounds, which strongly indicates that reversible associate formation is a general phenomenon for these complexes. These results are hoped to be exploited in novel therapeutic strategies aiming to use peptides as drug targets and control AMP bioactivity by directed assembly formation.

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What can we learn about functional importance of human antimicrobial peptide LL-37 in the oral environment from severe congenital neutropenia (Kostmann disease)?

Cited by 11 publications

References 45 publications

Antimicrobial peptides: Design, chemical synthesis, activity evaluation, and application

Antimicrobial peptides: Design, chemical synthesis, activity evaluation, and application

Injectable hydrogel as a carrier of vancomycin and a cathelicidin‐derived peptide for osteomyelitis treatment

Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System

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