9 results on '"Kentaro Sakaniwa"'
Search Results
2. Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists
- Author
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Yi Yang, Adam Csakai, Shuangshuang Jiang, Christina Smith, Hiromi Tanji, Jian Huang, Torey Jones, Kentaro Sakaniwa, Lindsey Broadwell, Chengrui Shi, Subada Soti, Umeharu Ohto, Yaohui Fang, Shu Shen, Fei Deng, Toshiyuki Shimizu, and Hang Yin
- Subjects
Science - Abstract
Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.
- Published
- 2021
- Full Text
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3. Rationally Designed Small-Molecule Inhibitors Targeting an Unconventional Pocket on the TLR8 Protein–Protein Interface
- Author
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Umeharu Ohto, Jing Li, Jian Huang, Toshiyuki Shimizu, Yi Yang, Kejun Yin, Kentaro Sakaniwa, Shuangshuang Jiang, Hang Yin, Shuting Zhang, and H. Tanji
- Subjects
01 natural sciences ,Peripheral blood mononuclear cell ,Protein Structure, Secondary ,Structure-Activity Relationship ,03 medical and health sciences ,Drug Delivery Systems ,Drug Discovery ,medicine ,Humans ,Protein Interaction Domains and Motifs ,030304 developmental biology ,0303 health sciences ,Dose-Response Relationship, Drug ,Chemistry ,Monocyte ,Protein protein ,TLR8 ,Small molecule ,0104 chemical sciences ,Cell biology ,010404 medicinal & biomolecular chemistry ,medicine.anatomical_structure ,Toll-Like Receptor 8 ,Cell culture ,Drug Design ,Leukocytes, Mononuclear ,Triazole derivatives ,Molecular Medicine - Abstract
Rational designs of small-molecule inhibitors targeting protein-protein interfaces have met little success. Herein, we have designed a series of triazole derivatives with a novel scaffold to specifically intervene with the interaction of TLR8 homomerization. In multiple assays, TH1027 was identified as a highly potent and specific inhibitor of TLR8. A successful solution of the X-ray crystal structure of TLR8 in complex with TH1027 provided an in-depth mechanistic insight into its binding mode, validating that TH1027 was located between two TLR8 monomers and recognized as an unconventional pocket, thereby preventing TLR8 from activation. Further biological evaluations showed that TH1027 dose-dependently suppressed the TLR8-mediated inflammatory responses in both human monocyte cell lines, peripheral blood mononuclear cells, and rheumatoid arthritis patient specimens, suggesting a strong therapeutic potential against autoimmune diseases.
- Published
- 2020
4. Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors 7 and 8
- Author
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Patrick Nordeen, Kentaro Sakaniwa, Rosaura Padilla-Salinas, Chuanjun Lu, Toshiyuki Shimizu, Shuting Zhang, Rachel Anderson, and Hang Yin
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0303 health sciences ,Endosome ,Guanosine ,DUAL (cognitive architecture) ,01 natural sciences ,Small molecule ,0104 chemical sciences ,Cell biology ,Imidazoquinoline ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Molecular Medicine ,Receptor ,030304 developmental biology - Abstract
Endosomal toll-like receptors (TLRs) 7 and 8 recognize viral single-stranded RNAs, a class of imidazoquinoline compounds, 8-oxo-adenosines, 8-aminobenzodiazepines, pyrimidines, and guanosine analog...
- Published
- 2019
5. Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists
- Author
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Torey Jones, H. Tanji, Umeharu Ohto, Kentaro Sakaniwa, Toshiyuki Shimizu, Shuangshuang Jiang, Hang Yin, Jian Huang, Subada Soti, Fei Deng, Chengrui Shi, Adam Csakai, Yaohui Fang, Yi Yang, Christina Smith, Lindsey J. Broadwell, and Shu Shen
- Subjects
Agonist ,genetic structures ,medicine.drug_class ,Science ,Inflammatory response ,General Physics and Astronomy ,Medicinal chemistry ,Inflammation ,Mechanism of action ,Calorimetry ,behavioral disciplines and activities ,01 natural sciences ,Article ,General Biochemistry, Genetics and Molecular Biology ,Structure-Activity Relationship ,03 medical and health sciences ,X-Ray Diffraction ,medicine ,Humans ,Drug discovery and development ,030304 developmental biology ,0303 health sciences ,Toll-like receptor ,Multidisciplinary ,Innate immune system ,010405 organic chemistry ,business.industry ,Small molecules ,Imidazoles ,General Chemistry ,TLR8 ,Tlr agonists ,Recombinant Proteins ,Toll-like receptors ,0104 chemical sciences ,Molecular Docking Simulation ,HEK293 Cells ,nervous system ,Toll-Like Receptor 8 ,Quinolines ,Cancer research ,RNA ,medicine.symptom ,business ,psychological phenomena and processes ,Signal Transduction - Abstract
Small-molecule modulators of TLR8 have drawn much interests as it plays pivotal roles in the innate immune response to single-stranded RNAs (ssRNAs) derived from viruses. However, their clinical uses are limited because they can invoke an uncontrolled, global inflammatory response. The efforts described herein culminate in the fortuitous discovery of a tetrasubstituted imidazole CU-CPD107 which inhibits R848-induced TLR8 signaling. In stark contrast, CU-CPD107 shows unexpected synergistic agonist activities in the presence of ssRNA, while CU-CPD107 alone is unable to influence TLR8 signaling. CU-CPD107’s unique, dichotomous behavior sheds light on a way to approach TLR agonists. CU-CPD107 offers the opportunity to avoid the undesired, global inflammation side effects that have rendered imidazoquinolines clinically irrelevant, providing an insight for the development of antiviral drugs., Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.
- Published
- 2021
6. Targeting the innate immune receptor TLR8 using small-molecule agents. Corrigendum
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Kentaro Sakaniwa and Toshiyuki Shimizu
- Subjects
Agonist ,Innate immune system ,Structural biology ,Structural Biology ,medicine.drug_class ,medicine ,Antagonist ,Biology ,TLR8 ,Receptor ,Small molecule ,Cell biology - Abstract
Three of the figures in the article by Sakaniwa & Shimizu [(2020), Acta Cryst. D76, 621–629] were incorrectly annotated. Corrected figures are published here.
- Published
- 2020
7. Discovery of Novel Small Molecule Dual Inhibitors Targeting Toll-Like Receptors
- Author
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Rosaura, Padilla-Salinas, Rachel, Anderson, Kentaro, Sakaniwa, Shuting, Zhang, Patrick, Nordeen, Chuanjun, Lu, Toshiyuki, Shimizu, and Hang, Yin
- Subjects
Oxadiazoles ,Dose-Response Relationship, Drug ,Reproducibility of Results ,Endosomes ,Crystallography, X-Ray ,High-Throughput Screening Assays ,Small Molecule Libraries ,Mice ,Structure-Activity Relationship ,HEK293 Cells ,RAW 264.7 Cells ,Toll-Like Receptor 7 ,Toll-Like Receptor 8 ,Animals ,Humans ,Anilides ,Molecular Targeted Therapy - Abstract
Endosomal toll-like receptors (TLRs)
- Published
- 2019
8. Small-molecule inhibition of TLR8 through stabilization of its resting state
- Author
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Jin Jin, Umeharu Ohto, Hang Yin, Kentaro Sakaniwa, Toshiyuki Shimizu, Shuangshuang Jiang, Nabanita Das, H. Tanji, Zhenyi Hu, Yanyan Bian, Shuting Zhang, and Jing Li
- Subjects
Models, Molecular ,0301 basic medicine ,Endosome ,Ligands ,Transfection ,Article ,Cell Line ,Proinflammatory cytokine ,Arthritis, Rheumatoid ,Small Molecule Libraries ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Binding site ,Receptor ,Molecular Biology ,Cell Proliferation ,Binding Sites ,Protein Stability ,Chemistry ,Synovial Membrane ,Cell Biology ,TLR7 ,Small molecule ,Immunity, Innate ,3. Good health ,Cell biology ,030104 developmental biology ,Biochemistry ,Toll-Like Receptor 8 ,030220 oncology & carcinogenesis ,TLR3 ,Leukocytes, Mononuclear ,Protein Multimerization - Abstract
Endosomal Toll-like receptors (TLR3, TLR7, TLR8, and TLR9) are highly analogous sensors for various viral or bacterial RNA and DNA molecular patterns. Nonetheless, few small molecules can selectively modulate these TLRs. In this manuscript, we identified the first human TLR8-specific small-molecule antagonists via a novel inhibition mechanism. Crystal structures of two distinct TLR8-ligand complexes validated a unique binding site on the protein-protein interface of the TLR8 homodimer. Upon binding to this new site, the small-molecule ligands stabilize the preformed TLR8 dimer in its resting state, preventing activation. As a proof of concept of their therapeutic potential, we have demonstrated that these drug-like inhibitors are able to suppress TLR8-mediated proinflammatory signaling in various cell lines, human primary cells, and patient specimens. These results not only suggest a novel strategy for TLR inhibitor design, but also shed critical mechanistic insight into these clinically important immune receptors.
- Published
- 2017
9. Small-Molecule TLR8 Antagonists via Structure-Based Rational Design
- Author
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Umeharu Ohto, Toshiyuki Shimizu, Kyoin Koo, Kentaro Sakaniwa, H. Tanji, Zhenyi Hu, Shuangshuang Jiang, Hang Yin, Albert Candia, Shuting Zhang, and Jean Chan
- Subjects
0301 basic medicine ,Clinical Biochemistry ,Chemical biology ,Computational biology ,Biology ,medicine.disease_cause ,Crystallography, X-Ray ,Biochemistry ,Peripheral blood mononuclear cell ,Article ,Protein–protein interaction ,Autoimmunity ,Autoimmune Diseases ,Small Molecule Libraries ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Drug Discovery ,medicine ,Animals ,Humans ,Receptor ,Molecular Biology ,Cells, Cultured ,Pharmacology ,Binding Sites ,Rational design ,TLR8 ,Small molecule ,Molecular Docking Simulation ,030104 developmental biology ,HEK293 Cells ,Toll-Like Receptor 8 ,030220 oncology & carcinogenesis ,Drug Design ,Molecular Medicine ,Computer-Aided Design - Abstract
Rational design of drug-like small-molecule ligands based on structural information of proteins remains a significant challenge in chemical biology. In particular, designs targeting protein-protein interfaces have met little success given the dynamic nature of the protein surfaces. Herein, we utilized the structure of a small-molecule ligand in complex with Toll-like receptor 8 (TLR8) as a model system due to TLR8's clinical relevance. Overactivation of TLR8 has been suggested to play a prominent role in the pathogenesis of various autoimmune diseases; however, there are still few small-molecule antagonists available, and our rational designs led to the discovery of six exceptionally potent compounds with ∼picomolar IC50 values. Two X-ray crystallographic structures validated the contacts within the binding pocket. A variety of biological evaluations in cultured cell lines, human peripheral blood mononuclear cells, and splenocytes from human TLR8-transgenic mice further demonstrated these TLR8 inhibitors' high efficacy, suggesting strong therapeutic potential against autoimmune disorders.
- Published
- 2018
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