Identification of indole scaffold-based dual inhibitors of NOD1 and NOD2

Plešec, Kaja Keček; Urbančič, Dunja; Gobec, Martina; Pekošak, Aleksandra; Tomašič, Tihomir; Anderluh, Marko; Mlinarič-Raščan, Irena

doi:10.1016/j.bmc.2016.08.044

Cited by 18 publications

(22 citation statements)

References 59 publications

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“…Suppressing NOD2 with NOD2 siRNA decreases autophagy induced by M. ovipneumoniae. NOD-IN-1 is a mixed inhibitor of NOD1 and NOD2 (25). To further verify the impact of NOD2 on M. ovipneumoniae-induced macrophage autophagy, RAW 264.7 cells were transfected with small interfering (siRNA)-control (NC) or siRNA-NOD2 and then infected with M. ovipneumoniae for 12 h. A decrease in NOD2 was observed after transfection with siRNA-NOD2-1 and siRNA-NOD3-3.…”

Section: Resultsmentioning

confidence: 99%

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NOD2/c-Jun NH ₂ -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy

Luo

et al. 2020

J Bacteriol

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Mycoplasma ovipneumoniae (M. ovipneumoniae) belongs to Mycoplasma, a genus containing the smallest self-replicating microorganisms, and causes infectious pleuropneumonia in goats and sheep. Nucleotide-binding oligomerization domain-containing protein (NOD2), an intracellular pattern recognition receptor, interacts with muramyl dipeptide (MDP) to recognize bacterial peptidoglycans and is involved in autophagy induction. However, there have been no reports about NOD recognition of mycoplasmas or about M. ovipneumoniae-induced autophagy. In this study, we sought to determine the role of NOD2 in M. ovipneumoniae-induced autophagy using western blot, immunofluorescence, real-time polymerase chain reaction (RT-PCR), and color change unit (CCU) analysis. M. ovipneumoniae infection markedly increased NOD2, but not increased NOD1 expression in Raw264.7. Treating Raw264.7 cells with MDP significantly increased colocalization of M. ovipneumoniae and LC3, whereas treatment with NOD inhibitor, NOD-IN-1, decreased colocalization of M. ovipneumoniae and LC3. Furthermore, suppressing NOD2 expression with siRNA-NOD2 failed to trigger M. ovipneumoniae-induced autophagy by detecting autophagy markers Atg5, Beclin1, and LC3-II. In addition, M. ovipneumoniae infection significantly increased the p-JNK/JNK, p-Bcl-2/Bcl-2, Beclin1, Atg5, and LC3-II ratios in Raw264.7 cells. Treatment with JNK inhibitor, SP600126, or siRNA-NOD2 did not increase this reaction. These findings suggested that M. ovipneumoniae infection activated NOD2, and both NOD2 and JNK pathway activation promoted M. ovipneumoniae-induced autophagy. This study provides new insight into the NOD2 reorganization mechanism and the pathogenesis of M. ovipneumoniae infection. Important Mycoplasma ovipneumoniae, which lacks a cell wall, causes infectious pleuropneumonia in goats and sheep. In the present study, we focused on the interaction between NOD and M. ovipneumoniae, as well as its association with autophagy. We showed for the first time that NOD2 was activated by M. ovipneumoniae even when peptidoglycans were not present. We also observed that both NOD2 and JNK pathway activation promoted M. ovipneumoniae-induced autophagy.

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Section: Resultsmentioning

confidence: 99%

“…MDP is an activator of NOD2, and NOD-IN-1 is a potent mixed inhibitor of NOD1 and NOD2 ( 25 ). To further test the involvement of NOD2 in M. ovipneumoniae -induced autophagy, we measured the colocalization of M. ovipneumoniae and LC3 in RAW 264.7 cells treated with MDP or NOD-IN-1.…”

Section: Resultsmentioning

confidence: 99%

NOD2/c-Jun NH ₂ -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy

Luo

et al. 2020

J Bacteriol

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“…Therefore, NOD receptors appear to be potentially important targets of therapeutic intervention in sepsis and septic shock. Presently, antagonists of NOD1 and NOD2 are being developed . Most of these compounds are derivatives of heterocyclic bicyclic compounds such as indole, purine, or benzimidazole .…”

Section: Potential Clinical Relevance Of Nod‐tlr Synergymentioning

confidence: 99%

“…Presently, antagonists of NOD1 and NOD2 are being developed . Most of these compounds are derivatives of heterocyclic bicyclic compounds such as indole, purine, or benzimidazole . Some of them are dual NOD1/NOD2 antagonists, whereas others are selective towards NOD1 or NOD2 .…”

Section: Potential Clinical Relevance Of Nod‐tlr Synergymentioning

confidence: 99%

“…Most of these compounds are derivatives of heterocyclic bicyclic compounds such as indole, purine, or benzimidazole . Some of them are dual NOD1/NOD2 antagonists, whereas others are selective towards NOD1 or NOD2 . Therapeutic efficacy of these drugs alone or in combination with anti‐LPS agents should be tested in preclinical models of sepsis and septic shock.…”

Section: Potential Clinical Relevance Of Nod‐tlr Synergymentioning

confidence: 99%

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Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

Pashenkov

Murugina

Будихина

et al. 2018

Journal of Leukocyte Biology

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Interactions between pattern recognition receptors (PRRs) shape innate immune responses to particular classes of pathogens. Here, we review interactions between TLRs and nucleotide‐binding oligomerization domain 1 and 2 (NOD1 and NOD2) receptors, two major groups of PRRs involved in innate recognition of bacteria. Most of experimental data both in vitro and in vivo suggest that NODs and TLRs synergize with each other at inducing the production of cytokines and antimicrobial peptides. Molecular mechanisms of this synergy remain poorly understood, although several scenarios can be proposed: (i) direct interactions of signaling pathways downstream of NODs and TLRs; (ii) mutual transcriptional regulation of unique components of NOD‐dependent and TLR‐dependent signaling pathways; and (iii) interactions at the post‐transcriptional level. Potential practical implications of NOD‐TLR synergy are dual. In sepsis, where synergistic effects probably contribute to excessive proinflammatory cytokine production, blockade of NOD1, and/or NOD2 in addition to TLR4 blockade may be required to achieve therapeutic benefit. On the other hand, synergistic combinations of relatively small doses of NOD and TLR agonists administered before infection could be used to boost innate resistance against bacterial pathogens.

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Flavonoid-rich extract of Chromolaena odorata modulate circulating GLP-1 in Wistar rats: computational evaluation of TGR5 involvement

et al. 2018

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Identification of indole scaffold-based dual inhibitors of NOD1 and NOD2

Cited by 18 publications

References 59 publications

NOD2/c-Jun NH ₂ -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy

NOD2/c-Jun NH ₂ -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

Flavonoid-rich extract of Chromolaena odorata modulate circulating GLP-1 in Wistar rats: computational evaluation of TGR5 involvement

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Identification of indole scaffold-based dual inhibitors of NOD1 and NOD2

Cited by 18 publications

References 59 publications

NOD2/c-Jun NH 2 -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy

NOD2/c-Jun NH 2 -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy

Synergistic interactions between NOD receptors and TLRs: Mechanisms and clinical implications

Flavonoid-rich extract of Chromolaena odorata modulate circulating GLP-1 in Wistar rats: computational evaluation of TGR5 involvement

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NOD2/c-Jun NH ₂ -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy

NOD2/c-Jun NH ₂ -Terminal Kinase Triggers Mycoplasma ovipneumoniae-Induced Macrophage Autophagy