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
近日,药学领域权威期刊《Acta Pharmaceutica Sinica B》(IF=14.8)在线发表了沈阳药科大学制药工程学院胡春教授课题组和中国香港中文大学邵鹏柱教授课题组在抗流感药物研究领域的最新成果,文章题目为“Design, synthesis and biologica...近日,药学领域权威期刊《Acta Pharmaceutica Sinica B》(IF=14.8)在线发表了沈阳药科大学制药工程学院胡春教授课题组和中国香港中文大学邵鹏柱教授课题组在抗流感药物研究领域的最新成果,文章题目为“Design, synthesis and biological evaluation of a novel class of indazole-containing compounds with potent anti-influenza activities targeting the PA-PB1interface”。流感病毒的高突变率使得抗流感药物耐药频发,流感治疗的选择受限。流感病毒聚合酶因其保守性、多重可靶向性等特点,成为抗流感药物开发的理想靶点。展开更多
近日,药学领域权威期刊《Acta Pharmaceutica Sinica B》(IF=14.8)在线发表了沈阳药科大学制药工程学院胡春教授课题组和香港中文大学邵鹏柱教授课题组在抗流感药物研究领域的最新成果,文章题目为“Design, synthesis and biological ev...近日,药学领域权威期刊《Acta Pharmaceutica Sinica B》(IF=14.8)在线发表了沈阳药科大学制药工程学院胡春教授课题组和香港中文大学邵鹏柱教授课题组在抗流感药物研究领域的最新成果,文章题目为“Design, synthesis and biological evaluation of a novel class of indazole-containing compounds with potent anti-influenza activities targeting the PA-PB1 interface”。展开更多
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.
文摘近日,药学领域权威期刊《Acta Pharmaceutica Sinica B》(IF=14.8)在线发表了沈阳药科大学制药工程学院胡春教授课题组和中国香港中文大学邵鹏柱教授课题组在抗流感药物研究领域的最新成果,文章题目为“Design, synthesis and biological evaluation of a novel class of indazole-containing compounds with potent anti-influenza activities targeting the PA-PB1interface”。流感病毒的高突变率使得抗流感药物耐药频发,流感治疗的选择受限。流感病毒聚合酶因其保守性、多重可靶向性等特点,成为抗流感药物开发的理想靶点。
文摘近日,药学领域权威期刊《Acta Pharmaceutica Sinica B》(IF=14.8)在线发表了沈阳药科大学制药工程学院胡春教授课题组和香港中文大学邵鹏柱教授课题组在抗流感药物研究领域的最新成果,文章题目为“Design, synthesis and biological evaluation of a novel class of indazole-containing compounds with potent anti-influenza activities targeting the PA-PB1 interface”。
