NF-κB Signaling and Inflammation—Drug Repurposing to Treat Inflammatory Disorders?
Abstract
:Simple Summary
Abstract
1. NF-κB Signaling in Inflammation
1.1. A Brief History of NF-κB Signaling in Inflammatory Diseases
1.2. NF-κB Signaling in Inflammatory Diseases
1.3. NF-κB Activity as a Druggable Target in Inflammatory Diseases
2. Drug Repurposing to Identify NF-κB Inhibitors
2.1. Why Do We Need New Anti-Inflammatory Drugs?
2.2. Approaches to Drug Repurposing
3. Computer-Based Drug Repurposing Strategies
Resource | Description | References |
---|---|---|
Databases and Libraries | ||
Drug Repurposing Hub | Annotated library of FDA-approved drugs, drugs undergoing clinical trials, and preclinical tool compounds | [88] |
DrugCentral | Online drug information resource containing 4714 drugs and 129,975 pharmaceuticals, providing up-to-date drug information, including a drug repositioning prioritization scheme for FDA-approved drugs | [89] |
CheMBL | Database of bioactive molecules with druglike properties, containing chemical, bioactivity and genomic data to aid translation of genomic information into effective new drugs | [90,91] |
ReDo_Trials Database | Database of active clincal trials investigating repurposed drugs for cancer therapy | [92] |
RepoDB | Database of approved and failed drugs and their indications | [93] |
ReFrame Database | Commercially available screening library of 12,000 molecules for use in high throughput cell-based repurposing assays | [94] |
Zinc | Library of >700,000 small molecules for use in computational screening | [95] |
COVID-19 Drug Repurposing Database (Excelra) | Commercially available database of approved drugs which can rapidly be entered into phase II or III trials against COVID-19 | [96] |
DrugRepurposing Online (Nimedicus) | Commercially available database of 9040 candidate repurposing compounds annotated with indications and mechanisms | [97] |
PROMISCUOUS | Publicly available database of 25,000 drugs annotated with drug-protein, protein-protein interactions, drug structural similarity and known side-effects | [98] |
Methods | ||
DeepDTNet | Deep learning system for identification of novel targets for drug repurposing in disease specific contexts | [99] |
AOPDEF | Deep learning system identifying molecular targets among known drugs on two external validation sets | [100] |
MBiRW | Computational method to identify novel indications for given drugs | [101] |
KinderMiner | Text mining method to identify repurposing candidates | [102] |
DrugQuest | Text mining method to identify simmilarities between DrugBank entries | [103] |
Semantic Link Association Prediction (SLAP) | Statistical algorithm to predict novel drug-target pairs | [104] |
3.1. Pharmacophore Modeling-Based Drug Repurposing
3.2. Artificial Intelligence-Aided Drug Repurposing
4. Experimental Approaches to Drug Repurposing
4.1. Target-Based Approaches to Drug Repurposing
4.2. Phenotypic Screening Approaches to Drug Repurposing in Cell Lines and Model Organisms
5. NF-κB as a Potential Target for Drug Development in CNS Inflammation
5.1. NF-κB Activation in T Cells in MS/EAE
5.2. Role of NF-κB Activation in Macrophages and Microglia in MS
Cell Type | Genotypic Alteration in NF-κB Signaling | Effect on Neuroinflammation | References |
---|---|---|---|
T cells | IKKβ deficient T cells | Resistance to EAE, impaired autoreactive T cell activation and expansion | [149] |
p50 deficient | Attenuated EAE incidence and severity, impaired Th1 and Th2 differentiation | [150] | |
c-Rel deficient | Resistance to EAE, defective Th1 and Th17 development | [148,151] | |
MALT1 deficient | Protection from EAE, absence of demyelination, proinflammatory cytokines and immune cell infiltration into spinal cord. Effector function of autoreactive Th17 cells impaired | [165,166] | |
CARMA1 deficient | Resistance to EAE, impaired Th17 differentiation | [167] | |
IκBαΔN | Resistance to EAE, reduced Th17 differentiation | [167] | |
NIK deficient | Protection from EAE due to DC function and independent from CD4+ T cell function | [168] | |
NIK deficient | Resistance to EAE, impaired Th17 differentiation | [152] | |
NIK deficient T cells | Attenuation of EAE, reduced generation of Th1 and Th17 cells, reduced immune cell infiltration | [153] | |
Macrophages/ Microglia | IκBα deficient | Exacerbated EAE, increased immune cell infiltration and myeloid-derived proinflammatory cytokines | [160] |
IKKβ deficient macrophages/ microglia | Attenuation of EAE, reduced immune cell infiltration, production of proinflammatory cytokines and permeability of the BBB. Increase in Tregs and decrease of Th1 and Th17 cells | [161,162] | |
TAK1 deficient microglia | Reduced CNS inflammation and neurodegeneration, NF-κB inhibition | [163] | |
TREM2 overexpressing myeloid precursor cells | Attenuation of EAE, reduced neurodegeneration, increase in anti-inflammatory cytokines and phagocytosis | [164] | |
A20 deficient microglia | Aggravated EAE, Nrp3 inflammasome activation, increase in immune cell infiltration and proinflammatory cytokine production | [169] | |
Astrocytes | IκBα overexpressing astrocytes | Attenuation of EAE, decreased immune cell infiltration and production of proinflammatory cytokines | [170,171,172] |
IKKβ deficient astrocytes | Protection from myelin loss in cuprizone-induced inflammation model | [173] | |
A20 deficient astrocytes | Aggravated EAE, increase in immune cell infiltration and proinflammatory cytokine production | [174,175] | |
Oligodendrocytes | IκBαΔN in oligodendrocytes | Aggravated EAE, reduced remyelination and oligodendrocyte death in cuprizone-induced inflammation model | [176] |
IKKβ deficient oligodendrocytes | No protection from demyelination in cuprizone-induced inflammation model | [173] | |
Neurons | IKKβ deficient neurons | Aggravated EAE, increased Th1 infiltration and proinflammatory cytokine production. Reduced production of neuroprotective factors | [177] |
IκBα overexpressing neurons | No effect on EAE progression or inflammation | [178] |
5.3. NF-κB Activation in CNS Cells in MS
5.4. Repurposing NF-κB Inhibitors to Treat CNS Inflammation
6. NF-κB as a Potential Target for Drug Development in Joint Inflammation
6.1. NF-κB Activation in Innate Immune Cells in RA
6.2. NF-κB Activation in T and B Cells in RA
6.3. Repurposing NF-κB Inhibitors to Treat Joint Inflammation
7. Drug Repurposing for Targeting Inflammation in COVID-19 Pneumonia
8. Problems with Progressing Repurposed Drugs to Clinical Applications
9. Conclusions and Future Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Stimulus | Receptor | NF-κB Pathway |
---|---|---|
LPS | TLR4 | Canonical |
TNF-α | TNFR1 | Canonical |
IL-1 | IL-1R | Canonical |
BAFF | BAFFR | Noncanonical |
CD40L | CD40 | Noncanonical |
RANKL | RANK | Noncanonical |
LTβ | LTβR | Noncanonical |
TNF | TNFR2 | Canonical/Noncanonical |
TWEAK | Fn14 | Canonical/Noncanonical |
EGF | EGFR | Atypical |
UV | CK2 | Atypical |
Compound | Original Indication | New Indication | Comments | References |
---|---|---|---|---|
Clemastine fumarate | Allergic reactions | MS | Promotes oligodendrocyte precursor cell differentiation and therefore myelin repair, reduces neuroinflammation in ALS model (inhibits NF-κB) | [51,52,53,54,55,56,57,58,59,60,61] |
Curcumin | Dietary supplement | COVID-19 | Protects and promotes repair of alveolar ATII cells in inflammatory lung injury model, increases Tregs, IL-10 and M2 macrophages in acute lung injury model, protects from cardiovascular injuries, reduces inflammation by inhibiting NF-κB | [62,63,64] |
Ibuprofen | Pain relief | SCI | Promotes axon growth and motor function improvement in spinal cord injury models by RhoA inhibition | [65,66,67] |
Indomethacin | Pain relief | SCI | Promotes axon growth in spinal cord lesion model by RhoA inhibition | [65,67] |
Resolvin D1 | - | Liver injury | Protects from IR-induced sterile liver inflammation by promoting M2 phenotype and efferocytosis in Kupffer cells, protects astrocytes and ameliorates cognitive impairment after TBI, inhibits inflammation and NF-κB signaling | [68,69,70,71,72] |
New Indication | Drug | Original Implication | Effect on NF-κB Signaling | Effect On Inflammation | References |
---|---|---|---|---|---|
MS | Imatinib mesylate | Cancer (CML, ALL, GIST, HES, CEL) | Inhibits IκB phosphorylation and DNA binding of NF-κB | Attenuates inflammation and enhances BBB integrity in EAE, Phase II clinical trial for MS | [183,184,185] |
Clemastine | Relief of allergy symptoms | Decreases NF-κB activity and TLR4 expression | Promotes oligodendrocyte differentiation and remyelination in EAE/MS, inhibits inflammation and microglial M1-like activation | [52,53,55,56,57,58,61] | |
Ibudilast | Asthma, stroke | Inhibits NF-κB activity (possibly by preventing nuclear translocation) | Reduces inflammation in rats with chronic cerebral reperfusion and MS patients, Phase II clinical trial for MS | [186,187,188,189] | |
Topotecan | Cancer (ovarian cancer, lung cancer, SCLC) | Inhibits IKKβ and thus IκBα degradation | Attenuates inflammation in EAE | [99] | |
RA | Ibrutinib | Cancer (MCL, CLL, WM) | Inhibits NF-κB nuclear translocation | Anti-inflammatory effects in models of RA, sepsis and diabetes | [190,191,192,193] |
Bortezomib | Cancer (MM, MCL) | Proteasome inhibitor, prevents degradation of IκBα | Anti-inflammatory effects in models of MS, RA, lupus erythematosus and colitis, promotes osteoblast activation and RA pathogenesis, Phase II clinical trial for RA | [194,195,196,197,198,199] [200,201] | |
TDZ | Schizophrenia, psychosis | Inhibits IKKβ phosphorylation and IκBα degradation | Attenuates inflammation in endotoxemia model | [83] | |
Dasatinib | Cancer (CML, ALL) | Inhibits phosphorylation of IKKα, p65/p100/p105 and c-Rel | Inhibits inflammation and bone erosion in CIA and human FLS, increases IL-10 in CIA | [122,202,203,204] | |
COVID-19 | Dexamethasone | Inflammatory conditions (RA, asthma, allergies etc.) | Induces the expression of IκBα | Reduces mortality in later stage COVID-19 patients | [205,206,207,208] |
Anakinra | Relief of RA symptoms | Prevents activation of IL-1R | Reduces hyperinflammation and mortality and improves clinical signs of COVID-19 | [209,210,211,212,213,214] |
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Roberti, A.; Chaffey, L.E.; Greaves, D.R. NF-κB Signaling and Inflammation—Drug Repurposing to Treat Inflammatory Disorders? Biology 2022, 11, 372. https://doi.org/10.3390/biology11030372
Roberti A, Chaffey LE, Greaves DR. NF-κB Signaling and Inflammation—Drug Repurposing to Treat Inflammatory Disorders? Biology. 2022; 11(3):372. https://doi.org/10.3390/biology11030372
Chicago/Turabian StyleRoberti, Annabell, Laura Elizabeth Chaffey, and David R. Greaves. 2022. "NF-κB Signaling and Inflammation—Drug Repurposing to Treat Inflammatory Disorders?" Biology 11, no. 3: 372. https://doi.org/10.3390/biology11030372
APA StyleRoberti, A., Chaffey, L. E., & Greaves, D. R. (2022). NF-κB Signaling and Inflammation—Drug Repurposing to Treat Inflammatory Disorders? Biology, 11(3), 372. https://doi.org/10.3390/biology11030372