The Chinese National Compound Library of Peking University （PKU-CNCL） is a new high-throughput screening collection aimed at driving precompetitive drug discovery and target validation, and is one of satellite libra...The Chinese National Compound Library of Peking University （PKU-CNCL） is a new high-throughput screening collection aimed at driving precompetitive drug discovery and target validation, and is one of satellite libraries of the Chinese National Compound Library （CNCL）. It is a chemical database containing binding, functional, and ADMET information for a large number of drug-like bioactive compounds. These data are manually abstracted from the primary literature on a regular basis, and further curated and standardized to maximize their quality and utility across a wide range of chemical biology and drug-discovery research problems. Currently, the database contains 54 000 bioactivity measurements for more than 100 000 compounds. Access, data downloads, and web services are available at： http：//www.pkucncl.cn.展开更多
The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design.In this study,we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-ba...The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design.In this study,we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-based design to target the PB1-binding interface on PA.Biological evaluation of these compounds through a viral yield reduction assay revealed that compounds 27 and 31 both had a low micromolar range of the half maximal effective concentration(EC_(50))values against A/WSN/33(H1N1)(8.03 mmol/L for 27;14.6 mmol/L for 31),while the most potent candidate 24 had an EC_(50) value of 690 nM.Compound 24 was effective against different influenza strains including a pandemic H1N1 strain and an influenza B strain.Mechanistic studies confirmed that compound 24 bound PA with a K_(d) which equals to 1.88 mmol/L and disrupted the binding of PB1 to PA.The compound also decreased the lung viral titre in mice.In summary,we have identified a potent anti-influenza candidate with potency comparable to existing drugs and is effective against different viral strains.The therapeutic options for influenza infection have been limited by the occurrence of antiviral resistance,owing to the high mutation rate of viral proteins targeted by available drugs.To alleviate the public health burden of this issue,novel anti-influenza drugs are desired.In this study,we present our discovery of a novel class of indazolecontaining compounds which exhibited favourable potency against both influenza A and B viruses.The EC_(50) of the most potent compounds were within low micromolar to nanomolar concentrations.Furthermore,we show that the mouse lung viral titre decreased due to treatment with compound 24.Thus our findings identify promising candidates for further development of anti-influenza drugs suitable for clinical use.展开更多
Recently,a collaborative research led by Weibo Yang and Jim Sun1 published in Cell Chemical Biology identified a potent and selective small molecule inhibitor(SMIP-30)for human protein phosphatase Mg^(2+)/Mn^(2+)-depe...Recently,a collaborative research led by Weibo Yang and Jim Sun1 published in Cell Chemical Biology identified a potent and selective small molecule inhibitor(SMIP-30)for human protein phosphatase Mg^(2+)/Mn^(2+)-dependent 1 A(PPM1A).They applied this chemical probe to determine the autophagy receptor p62 as a new substrate of PPM1A.展开更多
基金National High Technology Research and Development Program 863(Grant No.2012AA020308)grants from National Natural Science Foundation of China(Grant No.21272017)"Significant new drugs creation" special science and Technology Major project for Chinese National Chemical Library(CNCL)
文摘The Chinese National Compound Library of Peking University （PKU-CNCL） is a new high-throughput screening collection aimed at driving precompetitive drug discovery and target validation, and is one of satellite libraries of the Chinese National Compound Library （CNCL）. It is a chemical database containing binding, functional, and ADMET information for a large number of drug-like bioactive compounds. These data are manually abstracted from the primary literature on a regular basis, and further curated and standardized to maximize their quality and utility across a wide range of chemical biology and drug-discovery research problems. Currently, the database contains 54 000 bioactivity measurements for more than 100 000 compounds. Access, data downloads, and web services are available at： http：//www.pkucncl.cn.
基金supported by a Health and Medical Research Fund(HMRF),Hong Kong SAR(No.18170352,China)to Pang-Chui Shaw.
文摘The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design.In this study,we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-based design to target the PB1-binding interface on PA.Biological evaluation of these compounds through a viral yield reduction assay revealed that compounds 27 and 31 both had a low micromolar range of the half maximal effective concentration(EC_(50))values against A/WSN/33(H1N1)(8.03 mmol/L for 27;14.6 mmol/L for 31),while the most potent candidate 24 had an EC_(50) value of 690 nM.Compound 24 was effective against different influenza strains including a pandemic H1N1 strain and an influenza B strain.Mechanistic studies confirmed that compound 24 bound PA with a K_(d) which equals to 1.88 mmol/L and disrupted the binding of PB1 to PA.The compound also decreased the lung viral titre in mice.In summary,we have identified a potent anti-influenza candidate with potency comparable to existing drugs and is effective against different viral strains.The therapeutic options for influenza infection have been limited by the occurrence of antiviral resistance,owing to the high mutation rate of viral proteins targeted by available drugs.To alleviate the public health burden of this issue,novel anti-influenza drugs are desired.In this study,we present our discovery of a novel class of indazolecontaining compounds which exhibited favourable potency against both influenza A and B viruses.The EC_(50) of the most potent compounds were within low micromolar to nanomolar concentrations.Furthermore,we show that the mouse lung viral titre decreased due to treatment with compound 24.Thus our findings identify promising candidates for further development of anti-influenza drugs suitable for clinical use.
文摘Recently,a collaborative research led by Weibo Yang and Jim Sun1 published in Cell Chemical Biology identified a potent and selective small molecule inhibitor(SMIP-30)for human protein phosphatase Mg^(2+)/Mn^(2+)-dependent 1 A(PPM1A).They applied this chemical probe to determine the autophagy receptor p62 as a new substrate of PPM1A.
