As one of the most successful therapeutic target families,G protein-coupled receptors(GPCRs)have experienced a transformation from random ligand screening to knowledge-driven drug design.We are eye-witnessing tremendo...As one of the most successful therapeutic target families,G protein-coupled receptors(GPCRs)have experienced a transformation from random ligand screening to knowledge-driven drug design.We are eye-witnessing tremendous progresses made recently in the understanding of their structure-function relationships that facilitated drug development at an unprecedented pace.This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.展开更多
Interferons(IFNs) are cytokines with fundamental roles in resistance to infections, cancer and other diseases. Type-I IFNs, interferon α(IFN-α) and interferon β(IFN-β), act through a shared receptor complex(IFNAR)...Interferons(IFNs) are cytokines with fundamental roles in resistance to infections, cancer and other diseases. Type-I IFNs, interferon α(IFN-α) and interferon β(IFN-β), act through a shared receptor complex(IFNAR) comprised of IFNAR1 and IFNAR2 subunits. Binding of type-I IFN to IFNAR1 will robustly activate Janus activated kinase-signal transducer and activator of transcription(JAK-STAT)signaling pathway. Aberrant activation of the type-I IFN response results in a spectrum of disorders called interferonopathies. The purpose of this research is to develop an assay for high-throughput screening(HTS) of small molecule inhibitors of the type-I IFN signaling pathway. Inhibition of type-I IFN signaling can be beneficial in terms of therapeutic use and understanding the underlying mechanism of action. We report here a HTS campaign with the secreted embryonic alkaline phosphatase(SEAP) reporter gene assay against 32,000 compounds which yielded 25 confirmed hits. These compounds were subsequently characterized for their cytotoxicity, effects on STAT phosphorylation and activities in IFN regulatory factor(IRF) transcription.展开更多
基金The authors acknowledge funding support from the National Natural Science Foundation of China 81872915(to M.-W.W.),81773792(to D.Y.),81973373(to D.Y.),21704064(to Q.Z.),31971362(to W.S.),31971178(to S.Z.),and 31770796(to Y.J.)National Science&Technology Major Project of China-Key New Drug Creation and Manufacturing Program 2018ZX09735-001(to M.-W.W.),2018ZX09711002-002-005(to D.Y.),and 2018ZX09711002-002-002(to Y.J.)+4 种基金the National Key Basic Research Program of China 2018YFA0507000(to M.-W.W.,S.Z.,W.S.,and H.T.)Novo Nordisk-CAS Research Fund grant NNCAS-2017-1-CC(to D.Y.)The Belt and Road Master Fellowship program(to V.L.)UCAS Scholarship for International Students(to S.D.)and The CAS-TWAS President's Fellowship for International Doctoral Students(to E.Y.).
文摘As one of the most successful therapeutic target families,G protein-coupled receptors(GPCRs)have experienced a transformation from random ligand screening to knowledge-driven drug design.We are eye-witnessing tremendous progresses made recently in the understanding of their structure-function relationships that facilitated drug development at an unprecedented pace.This article intends to provide a comprehensive overview of this important field to a broader readership that shares some common interests in drug discovery.
基金partially supported by grants from Shanghai Science and Technology Development Fund (to MWW: 15DZ2291600)the Thousand Talents Program in China (to MWW: [2011]166)
文摘Interferons(IFNs) are cytokines with fundamental roles in resistance to infections, cancer and other diseases. Type-I IFNs, interferon α(IFN-α) and interferon β(IFN-β), act through a shared receptor complex(IFNAR) comprised of IFNAR1 and IFNAR2 subunits. Binding of type-I IFN to IFNAR1 will robustly activate Janus activated kinase-signal transducer and activator of transcription(JAK-STAT)signaling pathway. Aberrant activation of the type-I IFN response results in a spectrum of disorders called interferonopathies. The purpose of this research is to develop an assay for high-throughput screening(HTS) of small molecule inhibitors of the type-I IFN signaling pathway. Inhibition of type-I IFN signaling can be beneficial in terms of therapeutic use and understanding the underlying mechanism of action. We report here a HTS campaign with the secreted embryonic alkaline phosphatase(SEAP) reporter gene assay against 32,000 compounds which yielded 25 confirmed hits. These compounds were subsequently characterized for their cytotoxicity, effects on STAT phosphorylation and activities in IFN regulatory factor(IRF) transcription.
