N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor

Oxidative stress is thought to contribute to disease pathogenesis in the central nervous system (CNS) disease multiple sclerosis (MS). Myeloperoxidase (MPO), a potent peroxidase that generates toxic radicals and oxidants, is increased in the CNS during MS. However, the exact mechanism whereby MPO drives MS pathology is not known. We addressed this question by inhibiting MPO in mice with experimental autoimmune encephalomyelitis (EAE) using our non-toxic MPO inhibitor KYC. We found that therapeutic administration of KYC for five days starting at the peak of disease significantly attenuated EAE disease severity, reduced myeloid cell numbers and permeability of the blood-brain-barrier (BBB). These data indicate that inhibition of MPO by KYC restores BBB integrity thereby limiting migration of myeloid cells into the CNS that drive EAE pathogenesis. In addition, these observations indicate that KYC may be an effective therapeutic agent for the treatment of MS.

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“…2C). These data support our previous findings that the primary mechanism of action of KYC is inhibition of MPO (Zhang et al 2013a). …”

Section: Resultssupporting

confidence: 92%

“…Thus we developed a new class of MPO inhibitors and recently showed that N-acetyl lysyltyrosylcysteine amide (KYC) was a potent, highly specific and non-toxic inhibitor of MPO-dependent oxidant/free radical generation (Zhang et al 2013a). Here we evaluated the efficacy of KYC for the treatment of MS using EAE.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Zhang

Ray

Miller

et al. 2015

Journal of Neurochemistry

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“…KYC decreases MPO-dependent HOCl production; LDL and protein oxidation; stimulated PMN-dependent MPO activity; and MPO-dependent EC injury and cell death ( 11 ). Cell culture studies reveal KYC is not cytotoxic even when used at concentrations as high a 4 mM ( 11 ).…”

Section: Resultsmentioning

confidence: 99%

“…In the present report, control (AA) and SCD mice were treated with N-acetyl-lysyltyrosylcysteine-amide (KYC), a novel tripeptide inhibitor of MPO that dose-dependently inhibits MPO HOCl production, MPO-mediated LDL oxidation, and MPO-dependent EC injury and death ( 11 ). Our studies show that KYC decreases soluble L-selectin (sL-selectin), oxidative stress, and liver injury and that it improves vascular EC function in SCD mice.…”

Section: Liver Immunofl Uorescence Studies and 3-cltyr And 3-no 2 Tyrmentioning

confidence: 99%

Inhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice

Zhang¹,

Xu²,

Weihrauch³

et al. 2013

Journal of Lipid Research

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Although polymorphonuclear neutrophils (PMN) are well recognized for playing important roles in infl ammation in sickle cell disease (SCD), direct evidence linking myeloperoxidase (MPO) to impaired vascular endothelial cell (EC) function in SCD remains lacking. Over the last 25 years, only a handful of studies have been published suggesting that MPO may be involved. One of the fi rst reports, published in 1986, showed that vaso-occlusive crises increased PMN stickiness, an index of activation, in SCD patients ( 1 ). In 1993, plasma levels of MPO and C3d were reported to be higher in SCD patients than in controls, and these biomarkers inversely correlated with red cell hemoglobin ( 2 ). In 1996, PMN were shown to interact directly with the sickle red blood cell (RBC), and this interaction notably enhanced PMN activation ( 3 ). Later in 2002, it was reported that activated PMN increased sickle RBC retention in isolated rat lungs ( 4 ) and that MPO and 3-nitrotyrosine colocalized in sections of lungs from patients who died from complications associated with SCD ( 5 ). Evidence that stress increases MPO in SCD comes from studies showing that exercise induced a dual increase in plasma MPO and percentage of sickled cells in SCD patients ( 6 ). Finally, evidence linking the coagulation pathway to infl ammation in sickle cell anemia comes from studies showing that inhibiting tissue factor decreased MPO in the lungs of SCD mice ( 7 ). Although these reports and others ( 8-10 ) provide strong support for the idea that PMN activation and MPO play important roles in SCD, Abstract Activated leukocytes and polymorphonuclear neutrophils (PMN) release myeloperoxidase (MPO), which binds to endothelial cells (EC), is translocated, and generates oxidants that scavenge nitric oxide (NO) and impair EC function. To determine whether MPO impairs EC function in sickle cell disease (SCD), control (AA) and SCD mice were treated with N-acetyl-lysyltyrosylcysteine-amide (KYC). SCD humans and mice have high plasma MPO and soluble L-selectin (sL-selectin). KYC had no effect on MPO but de-

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“…Using a primary brain microvascular endothelial cell line, it was shown that MPO can directly alter permeability in vitro [120]. In our studies utilizing the novel MPO inhibitor N -acetyl lysyltyrosylcysteine amide (KYC) [121], we found that its daily administration starting at disease initiation did not alter the day of onset or the kinetics of the first seven days of disease progression after which disease progression stalled resulting in a significantly reduced peak and cumulative disease score [122]. These data indicate, that at least in EAE, MPO does not play an essential role in the process of peripheral CD4 T cell priming that is required for EAE onset.…”

Section: Mpo In Multiple Sclerosis (Ms)mentioning

confidence: 99%

Myeloperoxidase: A new player in autoimmunity

Strzępa

Pritchard

Dittel

2017

Cellular Immunology

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176

103

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Myeloperoxidase (MPO) is the most toxic enzyme found in the azurophilic granules of neutrophils. MPO utilizes H2O2 to generate hypochlorous acid (HClO) and other reactive moieties, which kill pathogens during infections. In contrast, in the setting of sterile inflammation, MPO and MPO-derived oxidants are thought to be pathogenic, promoting inflammation and causing tissue damage. In contrast, evidence also exists that MPO can limit the extent of immune responses. Elevated MPO levels and activity are observed in a number of autoimmune diseases including in the central nervous system (CNS) of multiple sclerosis (MS) and the joints of rheumatoid arthritis (RA) patients. A pathogenic role for MPO in driving autoimmune inflammation was demonstrated using mouse models. Mechanisms whereby MPO is thought to contribute to disease pathogenesis include tuning of adaptive immune responses and/or the induction of vascular permeability.

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N-acetyl lysyltyrosylcysteine amide inhibits myeloperoxidase, a novel tripeptide inhibitor

Cited by 43 publications

References 71 publications

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Inhibition of myeloperoxidase at the peak of experimental autoimmune encephalomyelitis restores blood–brain barrier integrity and ameliorates disease severity

Inhibition of myeloperoxidase decreases vascular oxidative stress and increases vasodilatation in sickle cell disease mice

Myeloperoxidase: A new player in autoimmunity

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