研究人員已經(jīng)發(fā)現(xiàn)了一系列的化合物,。
這些化合物顯示，它們有希望在瘧原蟲進(jìn)入血流之前還在肝臟中孵化的時(shí)候?qū)⑵錃纭?/p>
人們急需這樣的藥物來治療間日瘧原蟲 ,，這是在非洲以外地區(qū)的主要的瘧原蟲種類,。間日瘧原蟲與致命的惡性虐原蟲不同，因?yàn)樗鼤?huì)在肝臟中進(jìn)入一種“休眠期”,，這時(shí)該瘧原蟲被稱作是一種休眠子,。休眠子可在感染的蚊子叮咬了其宿主之后數(shù)月甚或數(shù)年時(shí)重新出現(xiàn)在血液之中。
間日瘧原蟲感染的慢性和長(zhǎng)時(shí)間持續(xù)的性質(zhì)對(duì)感染者的健康和經(jīng)濟(jì)福祉都會(huì)產(chǎn)生重大的影響,。
Stephan Meister及其同事應(yīng)用一種自動(dòng)化顯微鏡檢測(cè)方法來篩檢成千上萬種已知可殺滅血液期瘧原蟲的化合物,，希望能夠找到那些也能殺滅肝臟期瘧原蟲的化合物。他們發(fā)現(xiàn)了一系列的叫做咪唑嗪的可以口服并能阻止在小鼠模型中瘧原蟲在肝細(xì)胞內(nèi)發(fā)育的化合物,。(生物谷 Bioon.com)
doi:10.1126/science.1211936
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PMID:
Imaging of Plasmodium Liver Stages to Drive Next Generation Antimalarial Drug Discovery
Stephan Meister, David M. Plouffe, Kelli L. Kuhen, Ghislain M. C. Bonamy, Tao Wu, S.Whitney Barnes, Selina E. Bopp, Rachel Borboa, A. Taylor Bright, Jianwei Che, Steve Cohen, Neekesh V. Dharia, Kerstin Gagaring, Montip Gettayacamin, Perry Gordon, Todd Groessl, Nobutaka Kato, Marcus C. S. Lee, Case W. McNamara, David A. Fidock, Advait Nagle, Tae-gyu Nam, Wendy Richmond, Jason Roland, Matthias Rottmann, Bin Zhou, Patrick Froissard, Richard J. Glynne, Dominique Mazier, Jetsumon Sattabongkot, Peter G. Schultz, Tove Tuntland, John R. Walker, Yingyao Zhou, Arnab Chatterjee, Thierry T. Diagana, and Elizabeth A. Winzeler
Most malaria drug development focuses on parasite stages detected in red blood cells, even though to achieve eradication, next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4,000 commercially available compounds with previously demonstrated blood stage activity (IC50 < 1 µM), and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.
