Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain
Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Jay Chauhan [verfasserIn] |
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| Format: |
Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2015 |
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| Rechteinformationen: |
Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences |
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| Übergeordnetes Werk: |
Enthalten in: Proceedings of the National Academy of Sciences of the United States of America - Washington, DC : NAS, 1877, 112(2015), 17, Seite 5455-5460 |
|---|---|
| Übergeordnetes Werk: |
volume:112 ; year:2015 ; number:17 ; pages:5455-5460 |
| Links: |
|---|
| DOI / URN: |
10.1073/pnas.1422576112 |
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| Katalog-ID: |
OLC197026358X |
|---|
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| 245 | 1 | 0 | |a Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain |
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| 520 | |a Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. | ||
| 540 | |a Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences | ||
| 650 | 4 | |a Benzaldehydes - pharmacology | |
| 650 | 4 | |a RNA, Messenger - immunology | |
| 650 | 4 | |a Toll-Like Receptor 2 - immunology | |
| 650 | 4 | |a Toll-Like Receptor 6 - immunology | |
| 650 | 4 | |a Interleukin-8 - immunology | |
| 650 | 4 | |a Toll-Like Receptor 2 - genetics | |
| 650 | 4 | |a Signal Transduction - immunology | |
| 650 | 4 | |a Inflammation - chemically induced | |
| 650 | 4 | |a Toll-Like Receptor 6 - genetics | |
| 650 | 4 | |a Interleukin-8 - genetics | |
| 650 | 4 | |a Antioxidants - chemistry | |
| 650 | 4 | |a Toll-Like Receptor 1 - genetics | |
| 650 | 4 | |a Inflammation - immunology | |
| 650 | 4 | |a RNA, Messenger - genetics | |
| 650 | 4 | |a Benzaldehydes - chemistry | |
| 650 | 4 | |a Signal Transduction - drug effects | |
| 650 | 4 | |a Toll-Like Receptor 2 - antagonists & inhibitors | |
| 650 | 4 | |a Anti-Inflammatory Agents - chemistry | |
| 650 | 4 | |a Toll-Like Receptor 1 - immunology | |
| 650 | 4 | |a Inflammation - genetics | |
| 650 | 4 | |a Antioxidants - pharmacology | |
| 650 | 4 | |a Signal Transduction - genetics | |
| 650 | 4 | |a Anti-Inflammatory Agents - pharmacology | |
| 650 | 4 | |a Inflammation - drug therapy | |
| 650 | 4 | |a Crystal structure | |
| 650 | 4 | |a Cytokines | |
| 650 | 4 | |a Molecules | |
| 650 | 4 | |a RNA-protein interactions | |
| 650 | 4 | |a Cells | |
| 650 | 4 | |a Mutagenesis | |
| 700 | 0 | |a Greg A. Snyder |4 oth | |
| 700 | 0 | |a Tristan Dyson |4 oth | |
| 700 | 0 | |a Ryan S. Schwarz |4 oth | |
| 700 | 0 | |a Michelle H. W. Laird |4 oth | |
| 700 | 0 | |a Steven Fletcher |4 oth | |
| 700 | 0 | |a Stefanie N. Vogel |4 oth | |
| 700 | 0 | |a Shannon Greene |4 oth | |
| 700 | 0 | |a Pragnesh Mistry |4 oth | |
| 700 | 0 | |a Alexander D. MacKerell Jr |4 oth | |
| 700 | 0 | |a Tsan Sam Xiao |4 oth | |
| 700 | 0 | |a Vladimir Y. Toshchakov |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t Proceedings of the National Academy of Sciences of the United States of America |d Washington, DC : NAS, 1877 |g 112(2015), 17, Seite 5455-5460 |w (DE-627)129505269 |w (DE-600)209104-5 |w (DE-576)014909189 |x 0027-8424 |7 nnns |
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| 856 | 4 | 1 | |u http://dx.doi.org/10.1073/pnas.1422576112 |3 Volltext |
| 856 | 4 | 2 | |u http://www.pnas.org/content/112/17/5455.abstract |
| 856 | 4 | 2 | |u http://www.ncbi.nlm.nih.gov/pubmed/25870276 |
| 856 | 4 | 2 | |u http://search.proquest.com/docview/1680232398 |
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10.1073/pnas.1422576112 doi PQ20160211 (DE-627)OLC197026358X (DE-599)GBVOLC197026358X (PRQ)c2500-457022a9666b7d2f8e509367b231a0a2e2a37985f0cccca90e6cc44df2544d503 (KEY)0583363920150000112001705455inhibitionoftlr2signalingbysmallmoleculeinhibitors DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Jay Chauhan verfasserin aut Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Benzaldehydes - pharmacology RNA, Messenger - immunology Toll-Like Receptor 2 - immunology Toll-Like Receptor 6 - immunology Interleukin-8 - immunology Toll-Like Receptor 2 - genetics Signal Transduction - immunology Inflammation - chemically induced Toll-Like Receptor 6 - genetics Interleukin-8 - genetics Antioxidants - chemistry Toll-Like Receptor 1 - genetics Inflammation - immunology RNA, Messenger - genetics Benzaldehydes - chemistry Signal Transduction - drug effects Toll-Like Receptor 2 - antagonists & inhibitors Anti-Inflammatory Agents - chemistry Toll-Like Receptor 1 - immunology Inflammation - genetics Antioxidants - pharmacology Signal Transduction - genetics Anti-Inflammatory Agents - pharmacology Inflammation - drug therapy Crystal structure Cytokines Molecules RNA-protein interactions Cells Mutagenesis Greg A. Snyder oth Tristan Dyson oth Ryan S. Schwarz oth Michelle H. W. Laird oth Steven Fletcher oth Stefanie N. Vogel oth Shannon Greene oth Pragnesh Mistry oth Alexander D. MacKerell Jr oth Tsan Sam Xiao oth Vladimir Y. Toshchakov oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 17, Seite 5455-5460 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:17 pages:5455-5460 http://dx.doi.org/10.1073/pnas.1422576112 Volltext http://www.pnas.org/content/112/17/5455.abstract http://www.ncbi.nlm.nih.gov/pubmed/25870276 http://search.proquest.com/docview/1680232398 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 17 5455-5460 |
| spelling |
10.1073/pnas.1422576112 doi PQ20160211 (DE-627)OLC197026358X (DE-599)GBVOLC197026358X (PRQ)c2500-457022a9666b7d2f8e509367b231a0a2e2a37985f0cccca90e6cc44df2544d503 (KEY)0583363920150000112001705455inhibitionoftlr2signalingbysmallmoleculeinhibitors DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Jay Chauhan verfasserin aut Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Benzaldehydes - pharmacology RNA, Messenger - immunology Toll-Like Receptor 2 - immunology Toll-Like Receptor 6 - immunology Interleukin-8 - immunology Toll-Like Receptor 2 - genetics Signal Transduction - immunology Inflammation - chemically induced Toll-Like Receptor 6 - genetics Interleukin-8 - genetics Antioxidants - chemistry Toll-Like Receptor 1 - genetics Inflammation - immunology RNA, Messenger - genetics Benzaldehydes - chemistry Signal Transduction - drug effects Toll-Like Receptor 2 - antagonists & inhibitors Anti-Inflammatory Agents - chemistry Toll-Like Receptor 1 - immunology Inflammation - genetics Antioxidants - pharmacology Signal Transduction - genetics Anti-Inflammatory Agents - pharmacology Inflammation - drug therapy Crystal structure Cytokines Molecules RNA-protein interactions Cells Mutagenesis Greg A. Snyder oth Tristan Dyson oth Ryan S. Schwarz oth Michelle H. W. Laird oth Steven Fletcher oth Stefanie N. Vogel oth Shannon Greene oth Pragnesh Mistry oth Alexander D. MacKerell Jr oth Tsan Sam Xiao oth Vladimir Y. Toshchakov oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 17, Seite 5455-5460 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:17 pages:5455-5460 http://dx.doi.org/10.1073/pnas.1422576112 Volltext http://www.pnas.org/content/112/17/5455.abstract http://www.ncbi.nlm.nih.gov/pubmed/25870276 http://search.proquest.com/docview/1680232398 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 17 5455-5460 |
| allfields_unstemmed |
10.1073/pnas.1422576112 doi PQ20160211 (DE-627)OLC197026358X (DE-599)GBVOLC197026358X (PRQ)c2500-457022a9666b7d2f8e509367b231a0a2e2a37985f0cccca90e6cc44df2544d503 (KEY)0583363920150000112001705455inhibitionoftlr2signalingbysmallmoleculeinhibitors DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Jay Chauhan verfasserin aut Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Benzaldehydes - pharmacology RNA, Messenger - immunology Toll-Like Receptor 2 - immunology Toll-Like Receptor 6 - immunology Interleukin-8 - immunology Toll-Like Receptor 2 - genetics Signal Transduction - immunology Inflammation - chemically induced Toll-Like Receptor 6 - genetics Interleukin-8 - genetics Antioxidants - chemistry Toll-Like Receptor 1 - genetics Inflammation - immunology RNA, Messenger - genetics Benzaldehydes - chemistry Signal Transduction - drug effects Toll-Like Receptor 2 - antagonists & inhibitors Anti-Inflammatory Agents - chemistry Toll-Like Receptor 1 - immunology Inflammation - genetics Antioxidants - pharmacology Signal Transduction - genetics Anti-Inflammatory Agents - pharmacology Inflammation - drug therapy Crystal structure Cytokines Molecules RNA-protein interactions Cells Mutagenesis Greg A. Snyder oth Tristan Dyson oth Ryan S. Schwarz oth Michelle H. W. Laird oth Steven Fletcher oth Stefanie N. Vogel oth Shannon Greene oth Pragnesh Mistry oth Alexander D. MacKerell Jr oth Tsan Sam Xiao oth Vladimir Y. Toshchakov oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 17, Seite 5455-5460 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:17 pages:5455-5460 http://dx.doi.org/10.1073/pnas.1422576112 Volltext http://www.pnas.org/content/112/17/5455.abstract http://www.ncbi.nlm.nih.gov/pubmed/25870276 http://search.proquest.com/docview/1680232398 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 17 5455-5460 |
| allfieldsGer |
10.1073/pnas.1422576112 doi PQ20160211 (DE-627)OLC197026358X (DE-599)GBVOLC197026358X (PRQ)c2500-457022a9666b7d2f8e509367b231a0a2e2a37985f0cccca90e6cc44df2544d503 (KEY)0583363920150000112001705455inhibitionoftlr2signalingbysmallmoleculeinhibitors DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Jay Chauhan verfasserin aut Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Benzaldehydes - pharmacology RNA, Messenger - immunology Toll-Like Receptor 2 - immunology Toll-Like Receptor 6 - immunology Interleukin-8 - immunology Toll-Like Receptor 2 - genetics Signal Transduction - immunology Inflammation - chemically induced Toll-Like Receptor 6 - genetics Interleukin-8 - genetics Antioxidants - chemistry Toll-Like Receptor 1 - genetics Inflammation - immunology RNA, Messenger - genetics Benzaldehydes - chemistry Signal Transduction - drug effects Toll-Like Receptor 2 - antagonists & inhibitors Anti-Inflammatory Agents - chemistry Toll-Like Receptor 1 - immunology Inflammation - genetics Antioxidants - pharmacology Signal Transduction - genetics Anti-Inflammatory Agents - pharmacology Inflammation - drug therapy Crystal structure Cytokines Molecules RNA-protein interactions Cells Mutagenesis Greg A. Snyder oth Tristan Dyson oth Ryan S. Schwarz oth Michelle H. W. Laird oth Steven Fletcher oth Stefanie N. Vogel oth Shannon Greene oth Pragnesh Mistry oth Alexander D. MacKerell Jr oth Tsan Sam Xiao oth Vladimir Y. Toshchakov oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 17, Seite 5455-5460 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:17 pages:5455-5460 http://dx.doi.org/10.1073/pnas.1422576112 Volltext http://www.pnas.org/content/112/17/5455.abstract http://www.ncbi.nlm.nih.gov/pubmed/25870276 http://search.proquest.com/docview/1680232398 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 17 5455-5460 |
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10.1073/pnas.1422576112 doi PQ20160211 (DE-627)OLC197026358X (DE-599)GBVOLC197026358X (PRQ)c2500-457022a9666b7d2f8e509367b231a0a2e2a37985f0cccca90e6cc44df2544d503 (KEY)0583363920150000112001705455inhibitionoftlr2signalingbysmallmoleculeinhibitors DE-627 ger DE-627 rakwb eng 500 DNB 570 AVZ LING fid BIODIV fid Jay Chauhan verfasserin aut Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain 2015 Text txt rdacontent ohne Hilfsmittel zu benutzen n rdamedia Band nc rdacarrier Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. Nutzungsrecht: © COPYRIGHT 2015 National Academy of Sciences Benzaldehydes - pharmacology RNA, Messenger - immunology Toll-Like Receptor 2 - immunology Toll-Like Receptor 6 - immunology Interleukin-8 - immunology Toll-Like Receptor 2 - genetics Signal Transduction - immunology Inflammation - chemically induced Toll-Like Receptor 6 - genetics Interleukin-8 - genetics Antioxidants - chemistry Toll-Like Receptor 1 - genetics Inflammation - immunology RNA, Messenger - genetics Benzaldehydes - chemistry Signal Transduction - drug effects Toll-Like Receptor 2 - antagonists & inhibitors Anti-Inflammatory Agents - chemistry Toll-Like Receptor 1 - immunology Inflammation - genetics Antioxidants - pharmacology Signal Transduction - genetics Anti-Inflammatory Agents - pharmacology Inflammation - drug therapy Crystal structure Cytokines Molecules RNA-protein interactions Cells Mutagenesis Greg A. Snyder oth Tristan Dyson oth Ryan S. Schwarz oth Michelle H. W. Laird oth Steven Fletcher oth Stefanie N. Vogel oth Shannon Greene oth Pragnesh Mistry oth Alexander D. MacKerell Jr oth Tsan Sam Xiao oth Vladimir Y. Toshchakov oth Enthalten in Proceedings of the National Academy of Sciences of the United States of America Washington, DC : NAS, 1877 112(2015), 17, Seite 5455-5460 (DE-627)129505269 (DE-600)209104-5 (DE-576)014909189 0027-8424 nnns volume:112 year:2015 number:17 pages:5455-5460 http://dx.doi.org/10.1073/pnas.1422576112 Volltext http://www.pnas.org/content/112/17/5455.abstract http://www.ncbi.nlm.nih.gov/pubmed/25870276 http://search.proquest.com/docview/1680232398 GBV_USEFLAG_A SYSFLAG_A GBV_OLC FID-LING FID-BIODIV SSG-OLC-PHY SSG-OLC-CHE SSG-OLC-MAT SSG-OLC-FOR SSG-OLC-PHA SSG-OLC-DE-84 SSG-OPC-MAT SSG-OPC-FOR GBV_ILN_40 GBV_ILN_59 AR 112 2015 17 5455-5460 |
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Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain |
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Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain |
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Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. |
| abstractGer |
Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. |
| abstract_unstemmed |
Toll-like receptor (TLR) signaling is initiated by dimerization of intracellular Toll/IL-1 receptor resistance (TIR) domains. For all TLRs except TLR3, recruitment of the adapter, myeloid differentiation primary response gene 88 (MyD88), to TLR TIR domains results in downstream signaling culminating in proinflammatory cytokine production. Therefore, blocking TLR TIR dimerization may ameliorate TLR2-mediated hyperinflammatory states. The BB loop within the TLR TIR domain is critical for mediating certain protein-protein interactions. Examination of the human TLR2 TIR domain crystal structure revealed a pocket adjacent to the highly conserved P681 and G682 BB loop residues. Using computer-aided drug design (CADD), we sought to identify a small molecule inhibitor(s) that would fit within this pocket and potentially disrupt TLR2 signaling. In silico screening identified 149 compounds and 20 US Food and Drug Administration-approved drugs based on their predicted ability to bind in the BB loop pocket. These compounds were screened in HEK293T-TLR2 transfectants for the ability to inhibit TLR2-mediated IL-8 mRNA. C16H15NO4 (C29) was identified as a potential TLR2 inhibitor. C29, and its derivative, ortho-vanillin (o-vanillin), inhibited TLR2/1 and TLR2/6 signaling induced by synthetic and bacterial TLR2 agonists in human HEK-TLR2 and THP-1 cells, but only TLR2/1 signaling in murine macrophages. C29 failed to inhibit signaling induced by other TLR agonists and TNF-α. Mutagenesis of BB loop pocket residues revealed an indispensable role for TLR2/1, but not TLR2/6, signaling, suggesting divergent roles. Mice treated with o-vanillin exhibited reduced TLR2-induced inflammation. Our data provide proof of principle that targeting the BB loop pocket is an effective approach for identification of TLR2 signaling inhibitors. |
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Inhibition of TLR2 signaling by small molecule inhibitors targeting a pocket within the TLR2 TIR domain |
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