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DOI | 10.1038/s41467-019-08463-z |
A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission | |
Baker, David A.1; Stewart, Lindsay B.1; Large, Jonathan M.2; Bowyer, Paul W.1; Ansell, Keith H.2; Jimenez-Diaz, Mar-A B.3; El Bakkouri, Majida4,5; Birchall, Kristian2; Dechering, Koen J.6; Bouloc, Nathalie S.2; Coombs, Peter J.2; Whalley, David2; Harding, Denise J.2; Smiljanic-Hurley, Ela2; Wheldon, Mary C.2; Walker, Eloise M.1; Dessens, Johannes T.1; Lafuente, Maria Jose3; Sanz, Laura M.3; Gamo, Francisco-Javier3; Ferrer, Santiago B.3; Hui, Raymond4,5; Bousema, Teun7; Angulo-Barturen, I. Igo3; Merritt, Andy T.2; Croft, Simon L.1; Gutteridge, Winston E.1; Kettleborough, Catherine A.2; Osborne, Simon A.2 | |
2019-01-31 | |
发表期刊 | NATURE COMMUNICATIONS
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ISSN | 2041-1723 |
出版年 | 2017 |
卷号 | 8 |
文章类型 | Article |
语种 | 英语 |
国家 | England; Spain; Canada; Netherlands |
英文摘要 | To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000409394300004 |
WOS关键词 | PLASMODIUM-FALCIPARUM GAMETOCYTES ; ARTEMISININ-RESISTANT MALARIA ; PIPERAQUINE RESISTANCE ; PARASITES ; INHIBITORS ; ANTIMALARIALS ; MOSQUITOS ; INVASION ; CAMBODIA ; BERGHEI |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/204195 |
专题 | 资源环境科学 |
作者单位 | 1.London Sch Hyg & Trop Med, Fac Infect & Trop Dis, Keppel St, London WC1E 7HT, England; 2.LifeArc, Accelerator Bldg,Open Innovat Campus, Stevenage SG1 2FX, Herts, England; 3.GlaxoSmithKline, Tres Cantos Med Dev Campus Dis Developing World, Madrid 28760, Spain; 4.Univ Toronto, Struct Genom Consortium, MaRS South Tower,101 Coll St, Toronto, ON M5G 1L7, Canada; 5.Toronto Gen Hosp, Res Inst, 610 Univ Ave, Toronto, ON M5G 2M9, Canada; 6.TropIQ Hlth Sci, POB 9101, NL-6500 HB Nijmegen, Netherlands; 7.Radboud Univ Nijmegen, Dept Med Microbiol, Med Ctr, NL-6525 HP Nijmegen, Netherlands |
推荐引用方式 GB/T 7714 | Baker, David A.,Stewart, Lindsay B.,Large, Jonathan M.,et al. A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission[J]. NATURE COMMUNICATIONS,2019,8. |
APA | Baker, David A..,Stewart, Lindsay B..,Large, Jonathan M..,Bowyer, Paul W..,Ansell, Keith H..,...&Osborne, Simon A..(2019).A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission.NATURE COMMUNICATIONS,8. |
MLA | Baker, David A.,et al."A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission".NATURE COMMUNICATIONS 8(2019). |
条目包含的文件 | 条目无相关文件。 |
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