Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition
文献类型：期刊论文
| 作者 | Vavricka, Christopher J.6; Li, Qing6,7; Wu, Yan6; Qi, Jianxun6; Wang, Mingyang1,6; Liu, Yue6; Gao, Feng2; Liu, Jun6; Feng, Enguang3; He, Jianhua4 |
| 刊名 | PLOS PATHOGENS
 |
| 出版日期 | 2011-10 |
| 卷号 | 7期号:10 |
| ISSN号 | 1553-7366 |
| DOI | 10.1371/journal.ppat.1002249 |
| 文献子类 | Article |
| 英文摘要 | The 2009 H1N1 influenza pandemic (pH1N1) led to record sales of neuraminidase (NA) inhibitors, which has contributed significantly to the recent increase in oseltamivir-resistant viruses. Therefore, development and careful evaluation of novel NA inhibitors is of great interest. Recently, a highly potent NA inhibitor, laninamivir, has been approved for use in Japan. Laninamivir is effective using a single inhaled dose via its octanoate prodrug (CS-8958) and has been demonstrated to be effective against oseltamivir-resistant NA in vitro. However, effectiveness of laninamivir octanoate prodrug against oseltamivir-resistant influenza infection in adults has not been demonstrated. NA is classified into 2 groups based upon phylogenetic analysis and it is becoming clear that each group has some distinct structural features. Recently, we found that pH1N1 N1 NA (p09N1) is an atypical group 1 NA with some group 2-like features in its active site (lack of a 150-cavity). Furthermore, it has been reported that certain oseltamivir-resistant substitutions in the NA active site are group 1 specific. In order to comprehensively evaluate the effectiveness of laninamivir, we utilized recombinant N5 (typical group 1), p09N1 (atypical group 1) and N2 from the 1957 pandemic H2N2 (p57N2) (typical group 2) to carry out in vitro inhibition assays. We found that laninamivir and its octanoate prodrug display group specific preferences to different influenza NAs and provide the structural basis of their specific action based upon their novel complex crystal structures. Our results indicate that laninamivir and zanamivir are more effective against group 1 NA with a 150-cavity than group 2 NA with no 150-cavity. Furthermore, we have found that the laninamivir octanoate prodrug has a unique binding mode in p09N1 that is different from that of group 2 p57N2, but with some similarities to NA-oseltamivir binding, which provides additional insight into group specific differences of oseltamivir binding and resistance. |
| WOS关键词 | ANTIINFLUENZA VIRUS ACTIVITY ; ACTING NEURAMINIDASE INHIBITOR ; A H1N1 VIRUS ; DRUG DESIGN ; SIALIC-ACID ; MAXIMUM-LIKELIHOOD ; OSELTAMIVIR ; ZANAMIVIR ; ANALOGS ; N1 |
| 资助项目 | Ministry of Science and Technology, China (MOST)[2011CB504703] ; National Natural Science Foundation of China (NSFC)[81021003] ; Chinese Academy of Sciences[2010Y2SB12] ; NSFC[31050110147] |
| WOS研究方向 | Microbiology ; Parasitology ; Virology |
| 语种 | 英语 |
| WOS记录号 | WOS:000296734300005 |
| 出版者 | PUBLIC LIBRARY SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278375]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物发现与设计中心 |
| 通讯作者 | Vavricka, Christopher J. |
| 作者单位 | 1.Chinese Acad Sci, Grad Univ, Beijing, Peoples R China; 2.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100080, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Appl Phys, Shanghai, Peoples R China; 5.Chinese Acad Sci, Beijing Inst Life Sci, Beijing, Peoples R China 6.Chinese Acad Sci, Inst Microbiol, CAS Key Lab Pathogen Microbiol & Immunol, Beijing, Peoples R China; 7.Univ Sci & Technol China, Sch Life Sci, Hefei 230026, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Vavricka, Christopher J.,Li, Qing,Wu, Yan,et al. Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition[J]. PLOS PATHOGENS,2011,7(10). |
| APA | Vavricka, Christopher J..,Li, Qing.,Wu, Yan.,Qi, Jianxun.,Wang, Mingyang.,...&Gao, George F..(2011).Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition.PLOS PATHOGENS,7(10). |
| MLA | Vavricka, Christopher J.,et al."Structural and Functional Analysis of Laninamivir and its Octanoate Prodrug Reveals Group Specific Mechanisms for Influenza NA Inhibition".PLOS PATHOGENS 7.10(2011). |
入库方式： OAI收割
来源：上海药物研究所
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