A Novel Antiparasitic Compound Kills Ring-Stage Plasmodium falciparum and Retains Activity Against Artemisinin-Resistant Parasites

被引：7

作者：

Clements, Rebecca L. ^{[1
,2
]}

Streva, Vincent ^{[2
]}

Dumoulin, Peter ^{[3
]}

Huang, Weigang ^{[4
]}

Owens, Edward ^{[5
]}

Raj, Dipak K. ^{[7
]}

Burleigh, Barbara ^{[3
]}

Llinas, Manuel ^{[5
,8
]}

Winzeler, Elizabeth A. ^{[6
]}

Zhang, Qisheng ^{[4
]}

Dvorin, Jeffrey D. ^{[2
,9
]}

机构：

[1] Harvard Med Sch, Biol & Biomed Sci, Boston, MA 02115 USA

[2] Boston Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA

[3] Harvard TH Chan Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA USA

[4] Univ N Carolina, Div Chem Biol & Med Chem, Chapel Hill, NC 27515 USA

[5] Penn State Univ, Huck Ctr Malaria Res, University Pk, PA 16802 USA

[6] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA

[7] Brown Univ, Rhode Isl Hosp, Med Sch, Ctr Int Hlth Res, Providence, RI 02903 USA

[8] Penn State Univ, Dept Chem, University Pk, PA USA

[9] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

来源：

JOURNAL OF INFECTIOUS DISEASES | 2020年 / 221卷 / 06期

基金：

美国国家卫生研究院; 比尔及梅琳达.盖茨基金会;

关键词：

antimalarial; artemisinin resistance; malaria; Plasmodium falciparum; ring-stage survival;

D O I：

10.1093/infdis/jiz534

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Spreading antimalarial resistance threatens effective treatment of malaria, an infectious disease caused by Plasmodium parasites. We identified a compound, BCH070, that inhibits asexual growth of multiple antimalarial-resistant strains of Plasmodium falciparum (half maximal inhibitory concentration [IC50] = 1-2 mu M), suggesting that BCH070 acts via a novel mechanism of action. BCH070 preferentially kills early ring-form trophozoites, and, importantly, equally inhibits ring-stage survival of wild-type and artemisinin-resistant parasites harboring the PfKelch13:C580Y mutation. Metabolomic analysis demonstrates that BCH070 likely targets multiple pathways in the parasite. BCH070 is a promising lead compound for development of new antimalarial combination therapy that retains activity against artemisinin-resistant parasites.

引用

页码：956 / 962

页数：7

共 15 条

[1]

Absalon S, 2018, MBIO, V9, DOI [10.1128/mBio.00130-18, 10.1128/mbio.00130-18]

[2] Metabolomic Profiling of the Malaria Box Reveals Antimalarial Target Pathways [J].

Allman, Erik L. ;

Painter, Heather J. ;

Samra, Jasmeet ;

Carrasquilla, Manuela ;

Llinas, Manuel .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2016, 60 (11) :6635-6649

[3] Flow Cytometry-Based Analysis of Artemisinin-Resistant Plasmodium falciparum in the Ring-Stage Survival Assay [J].

Amaratunga, Chanaki ;

Neal, Aaron T. ;

Fairhurst, Rick M. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2014, 58 (08) :4938-4940

[4]

[Anonymous], World Malaria Report 2018

[5] A molecular marker of artemisinin-resistant Plasmodium falciparum malaria [J].

Ariey, Frederic ;

Witkowski, Benoit ;

Amaratunga, Chanaki ;

Beghain, Johann ;

Langlois, Anne-Claire ;

Khim, Nimol ;

Kim, Saorin ;

Duru, Valentine ;

Bouchier, Christiane ;

Ma, Laurence ;

Lim, Pharath ;

Leang, Rithea ;

Duong, Socheat ;

Sreng, Sokunthea ;

Suon, Seila ;

Chuor, Char Meng ;

Bout, Denis Mey ;

Menard, Sandie ;

Rogers, William O. ;

Genton, Blaise ;

Fandeur, Thierry ;

Miotto, Olivo ;

Ringwald, Pascal ;

Le Bras, Jacques ;

Berry, Antoine ;

Barale, Jean-Christophe ;

Fairhurst, Rick M. ;

Benoit-Vical, Franoise ;

Mercereau-Puijalon, Odile ;

Menard, Didier .

NATURE, 2014, 505 (7481) :50-+

[6] Plasmodium falciparum Transfected with Ultra Bright NanoLuc Luciferase Offers High Sensitivity Detection for the Screening of Growth and Cellular Trafficking Inhibitors [J].

Azevedo, Mauro F. ;

Nie, Catherine Q. ;

Elsworth, Brendan ;

Charnaud, Sarah C. ;

Sanders, Paul R. ;

Crabb, Brendan S. ;

Gilson, Paul R. .

PLOS ONE, 2014, 9 (11)

[7] A broad analysis of resistance development in the malaria parasite [J].

Corey, Victoria C. ;

Lukens, Amanda K. ;

Istvan, Eva S. ;

Lee, Marcus C. S. ;

Franco, Virginia ;

Magistrado, Pamela ;

Coburn-Flynn, Olivia ;

Sakata-Kato, Tomoyo ;

Fuchs, Olivia ;

Gnadig, Nina F. ;

Goldgof, Greg ;

Linares, Maria ;

Gomez-Lorenzo, Maria G. ;

De Cozar, Cristina ;

Jose Lafuente-Monasterio, Maria ;

Prats, Sara ;

Meister, Stephan ;

Tanaseichuk, Olga ;

Wree, Melanie ;

Zhou, Yingyao ;

Willis, Paul A. ;

Gamo, Francisco-Javier ;

Goldberg, Daniel E. ;

Fidock, David A. ;

Wirth, Dyann F. ;

Winzeler, Elizabeth A. .

NATURE COMMUNICATIONS, 2016, 7

[8] Optimization of 2-Anilino 4-Amino Substituted Quinazolines into Potent Antimalarial Agents with Oral in Vivo Activity [J].

Gilson, Paul R. ;

Tan, Cyrus ;

Jarman, Kate E. ;

Lowes, Kym N. ;

Curtis, Joan M. ;

Nguyen, William ;

Di Rago, Adrian E. ;

Bullen, Hayley E. ;

Prinz, Boris ;

Duffy, Sandra ;

Baell, Jonathan B. ;

Hutton, Craig A. ;

Subroux, Helene Jousset ;

Crabb, Brendan S. ;

Avery, Vicky M. ;

Cowman, Alan F. ;

Sleebs, Brad E. .

JOURNAL OF MEDICINAL CHEMISTRY, 2017, 60 (03) :1171-1188

[9] The cytoplasmic prolyl-tRNA synthetase of the malaria parasite is a dual-stage target of febrifugine and its analogs [J].

Herman, Jonathan D. ;

Pepper, Lauren R. ;

Cortese, Joseph F. ;

Estiu, Guillermina ;

Galinsky, Kevin ;

Zuzarte-Luis, Vanessa ;

Derbyshire, Emily R. ;

Ribacke, Ulf ;

Lukens, Amanda K. ;

Santos, Sofia A. ;

Patel, Vishal ;

Clish, Clary B. ;

Sullivan, William J., Jr. ;

Zhou, Huihao ;

Bopp, Selina E. ;

Schimmel, Paul ;

Lindquist, Susan ;

Clardy, Jon ;

Mota, Maria M. ;

Keller, Tracy L. ;

Whitman, Malcolm ;

Wiest, Olaf ;

Wirth, Dyann F. ;

Mazitschek, Ralph .

SCIENCE TRANSLATIONAL MEDICINE, 2015, 7 (288)

[10] Targeting Plasmodium PI(4)K to eliminate malaria [J].

McNamara, Case W. ;

Lee, Marcus C. S. ;

Lim, Chek Shik ;

Lim, Siau Hoi ;

Roland, Jason ;

Nagle, Advait ;

Simon, Oliver ;

Yeung, Bryan K. S. ;

Chatterjee, Arnab K. ;

McCormack, Susan L. ;

Manary, Micah J. ;

Zeeman, Anne-Marie ;

Dechering, Koen J. ;

Kumar, T. R. Santha ;

Henrich, Philipp P. ;

Gagaring, Kerstin ;

Ibanez, Maureen ;

Kato, Nobutaka ;

Kuhen, Kelli L. ;

Fischli, Christoph ;

Rottmann, Matthias ;

Plouffe, David M. ;

Bursulaya, Badry ;

Meister, Stephan ;

Rameh, Lucia ;

Trappe, Joerg ;

Haasen, Dorothea ;

Timmerman, Martijn ;

Sauerwein, Robert W. ;

Suwanarusk, Rossarin ;

Russell, Bruce ;

Renia, Laurent ;

Nosten, Francois ;

Tully, David C. ;

Kocken, Clemens H. M. ;

Glynne, Richard J. ;

Bodenreider, Christophe ;

Fidock, David A. ;

Diagana, Thierry T. ;

Winzeler, Elizabeth A. .

NATURE, 2013, 504 (7479) :248-+

← 1 2 →