The 12/15-lipoxygenase as an emerging therapeutic target for Alzheimer's disease

Joshi, Yash B.; Giannopoulos, Phillip F.; Praticò, Domenico

doi:10.1016/j.tips.2015.01.005

Cited by 68 publications

(36 citation statements)

References 57 publications

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“…Finally, 3xTg mice receiving systemic administration of a selective inhibitor of L-12/15 LO showed significant reductions in Aβ deposition, phosphorylation of tau, and improvements of memory over those receiving placebo [10]. Together, these data have led to the suggestion that inhibition of L-12/15 LO may be a viable therapeutic strategy for the treatment of stroke [53] and AD [21]. …”

Section: Discussionmentioning

confidence: 99%

Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity

Akumuo

Yang

et al. 2017

Neuroscience Letters

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Considerable evidence supports a contributory role for leukocyte-type 12/15 Lipoxygenase (L-12/15 LO) in mediating hippocampal and cortical neuronal injury in models of Alzheimer’s disease and stroke. Whether L-12/15 LO contributes to neuronal injury in a model of Huntington’s disease (HD) has yet to be determined. HD is characterized by marked striatal neuronal loss, which can be mimicked in humans and animals by inhibition of mitochondrial complex II using 3-Nitropropionic acid (3-NP). Herein, we compared histological and behavioral outcomes between mice that were wild-type or null for L-12/15 LO following systemic injection of 3NP. We found that mice deficient in L-12/15 LO had a higher incidence of striatal lesions coincident with an increase in morbidity as compared to their wild-type littermate controls. This could not be explained by differential metabolism of 3-NP as striatal succinate dehydrogenase activity was inhibited to the same extent in both genotypes. The present results show that deleting L-12/15 LO is detrimental to the striatum in the setting of chronic, systemic 3-NP exposure and are consistent with the overall conclusion that region-specific effects may determine the ultimate outcome of L-12/15 LO activation in the setting of brain injury.

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Section: Discussionmentioning

confidence: 99%

Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity

Akumuo

Yang

et al. 2017

Neuroscience Letters

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“…[11,21–23] In addition, another 15-LOX-1 inhibitor, PD-146176 , has been found to mitigate the effects of the AD phenotype. [19] However, many of these inhibitors suffer from low inhibitory potency and/or poor physicochemical properties, such as a high logP value, which limits their potential therapeutic value.…”

Section: Introductionmentioning

confidence: 99%

Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties

Eleftheriadis

Poelman

Leus

et al. 2016

European Journal of Medicinal Chemistry

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The enzyme 15-lipoxygenase-1 (15-LOX-1) plays a dual role in diseases with an inflammatory component. On one hand 15-LOX-1 plays a role in pro-inflammatory gene expression and on the other hand it has been shown to be involved in central nervous system (CNS) disorders by its ability to mediate oxidative stress and damage of mitochondrial membranes under hypoxic conditions. In order to further explore applications in the CNS, novel 15-LOX-1 inhibitors with favorable physicochemical properties need to be developed. Here, we present Substitution Oriented fragment Screening (SOS) in combination with Multi Component Chemistry (MCR) as an effective strategy to identify a diversely substituted small heterocyclic inhibitors for 15-LOX-1, denoted ThioLox, with physicochemical properties superior to previously identified inhibitors. Ex vivo biological evaluation in precision-cut lung slices (PCLS) showed inhibition of pro-inflammatory gene expression and in vitro studies on neuronal HT-22 cells showed a strong protection against glutamate toxicity for this 15-LOX-1 inhibitor. This provides a novel approach to identify novel small with favorable physicochemical properties for exploring 15-LOX-1 as a drug target in inflammatory diseases and neurodegeneration.

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“…15-LOX-1 is an important mammalian lipoxygenase that plays a role in the biosynthesis of 15-HPETE, 15-HETE, leukotrienes, lipoxins and eoxins. Several studies describe a role for 15-LOX-1 in allergic airway diseases [12][13][14][15], chronic airway inflammation [16], atherosclerosis [17], cancer [18,19] and more recently in various CNS diseases [20][21][22][23][24][25][26][27][28][29] like Alzheimer's and Parkinson's diseases as well as stroke. Therefore, this enzyme gained attention as a potential drug target and several classes of inhibitors have been described.…”

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confidence: 99%

“…Therefore, this enzyme gained attention as a potential drug target and several classes of inhibitors have been described. [22,[24][25][26][27][30][31][32][33][34][35][36][37][38] Development of activity-based probes for target enzymes start from irreversible mechanismbased enzyme inhibitors. For soybean lipoxygenase, structural analogs of PUFAs have been reported in which the cis-alkenes are replaced by alkynes that proved to be irreversible inactivators of LOX enzymes.…”

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confidence: 99%

“…In our study,h uman 15-lipoxygenase-1 (15-LOX-1) was selected as as tarting point for the development of activitybased probes for this class of enzymes.1 5-LOX-1 is an important mammalian lipoxygenase that plays ar ole in the biosynthesis of 15-HPETE, 15-HETE, leukotrienes,l ipoxins, and eoxins.S everal reports describe ar ole for 15-LOX-1 in allergic airway diseases, [12][13][14][15] chronic airway inflammation, [16] atherosclerosis, [17] cancer, [18,19] and more recently various CNS diseases, [20][21][22][23][24][25][26][27][28][29] such as Alzheimersand Parkinsonsdiseases as well as stroke.T herefore,t his enzyme gained attention as apotential drug target, and several classes of inhibitors have been described. [22,[24][25][26][27][30][31][32][33][34][35][36][37][38] Thed evelopment of activity-based probes for target enzymes starts from irreversible mechanism-based enzyme inhibitors.F or soybean lipoxygenase,s tructural analogues of PUFAs in which the cis alkenes were replaced with alkynes were reported to be irreversible inactivators of LOX enzymes. [39,40] Inactivation is expected to proceed through single-electron oxidation of the bispropargylic carbon atom, thus resulting in an allene radical that is highly reactive and binds covalently to the active site of the enzyme.W eaimed to use this type of inhibitor as as tarting structure to develop activity-based probes for LOX enzymes.…”

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confidence: 99%

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Activity‐Based Probes for 15‐Lipoxygenase‐1

et al. 2016

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Human 15-lipoxygenase-1 (15-LOX-1) plays an important role in several inflammatory lung diseases such as asthma, COPD and chronic bronchitis as well as in various CNS diseases like Alzheimer's, Parkinson's and stroke. Activity-based probes of 15-LOX-1 are required to explore the role of this enzyme further and to enable drug discovery. In this study, we developed the first 15-LOX-1 activity-based probe as an efficient chemical tool for activity-based labeling of recombinant 15-LOX-1 that also provides 15-LOX-1 dependent labeling in cell lysates and tissue samples. Mimicking the natural substrate of the enzyme, we designed activity-based probes that covalently bind to the active enzyme and include a terminal alkene as chemical reporter for bioorthogonal linkage of a detectable functionality via the oxidative Heck reaction. We believe that the activity-based labeling of 15-LOX-1 will enable the investigation and identification of this enzyme in complex biological samples, which opens completely new opportunities for drug discovery. Keywords15-LOX-1; activity-based probes; Kitz-Wilson plots; enzyme kinetics; irreversible inhibition Activity-based protein profiling (ABPP) has become a powerful method for the analysis of enzyme function and the selectivity of enzyme inhibitors in complex disease models.[1] In ABPP, small molecule substrate analogues, known as activity-based probes, are used to covalently bind to the active site of enzymes depending on their activity. Currently, many research groups use ABPP to investigate various enzyme classes, like cysteine proteases [2][3][4], serine hydrolases [5,6] Development of activity-based probes for target enzymes start from irreversible mechanismbased enzyme inhibitors. For soybean lipoxygenase, structural analogs of PUFAs have been reported in which the cis-alkenes are replaced by alkynes that proved to be irreversible inactivators of LOX enzymes. [39,40] Inactivation is expected to proceed through single electron oxidation of the bis-propargylic carbon resulting in an allene radical that is highly reactive and binds covalently to the enzyme's active site. We aimed to use this type of inhibitor as starting structure to develop activity based probes for LOX enzymes.Mimicking the natural 15-LOX-1 substrate, linoleic acid, inhibitors were designed incorporating a bis-alkyne core structure and their binding properties were investigated.[39,40] After modeling studies, in contrast with the previous inhibitors we shift the position of the bis-alkyne moiety from 9,12 to the 5,8 position due to structural differences in the active sites between the two enzymes ( Figure S9) but also aiming to yield less lipophilic compounds. Next, we developed ABPP probes that include both a bis-alkyne functionality for covalent linkage to the active enzyme and a terminal alkene as chemical reporter for bioorthogonal linkage of a detectable functionality (Figure 1). Application of a terminal alkene as chemical reporter and not the more commonly used terminal alkyne enables straightforward ...

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The 12/15-lipoxygenase as an emerging therapeutic target for Alzheimer's disease

Cited by 68 publications

References 57 publications

Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity

Mice deficient in L-12/15 lipoxygenase show increased vulnerability to 3-nitropropionic acid neurotoxicity

Design of a novel thiophene inhibitor of 15-lipoxygenase-1 with both anti-inflammatory and neuroprotective properties

Activity‐Based Probes for 15‐Lipoxygenase‐1

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