Development of Toxoplasma gondii Calcium-Dependent Protein Kinase 1 (TgCDPK1) Inhibitors with Potent Anti-Toxoplasma Activity

被引：91

作者：

Johnson, Steven M. ^{[2
]}

Murphy, Ryan C. ^{[2
]}

Geiger, Jennifer A. ^{[4
]}

DeRocher, Amy E. ^{[4
]}

Zhang, Zhongsheng ^{[3
]}

Ojo, Kayode K. ^{[1
]}

Larson, Eric T. ^{[3
]}

Perera, B. Gayani K. ^{[2
]}

Dale, Edward J. ^{[2
]}

He, Panqing ^{[1
]}

Reid, Molly C. ^{[1
]}

Fox, Anna M. W. ^{[1
]}

Mueller, Natascha R. ^{[1
]}

Merritt, Ethan A. ^{[3
]}

Fan, Erkang ^{[3
]}

Parsons, Marilyn ^{[4
,5
]}

Van Voorhis, Wesley C. ^{[1
,5
]}

Maly, Dustin J. ^{[2
]}

机构：

[1] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA 98105 USA

[2] Univ Washington, Dept Chem, Seattle, WA 98195 USA

[3] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[4] Seattle Biomed Res Inst, Seattle, WA 98109 USA

[5] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 05期

关键词：

UNITED-STATES; INFECTION; DISCOVERY; ANIMALS; HUMANS;

D O I：

10.1021/jm201713h

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Toxoplasmosis is a disease of prominent health concern that is caused by the protozoan parasite Toxoplasma gondii. Proliferation of T. gondii is dependent on its ability to invade host cells, which is mediated in part by calcium-dependent protein kinase 1 (CDPK1). We have developed ATP competitive inhibitors of TgCDPK1 that block invasion of parasites into host cells, preventing their proliferation. The presence of a unique glycine gatekeeper residue in TgCDPK1 permits selective inhibition of the parasite enzyme over human kinases. These potent TgCDPK1 inhibitors do not inhibit the growth of human cell lines and represent promising candidates as toxoplasmosis therapeutics.

引用

页码：2416 / 2426

页数：11

共 22 条

[11] Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma [J].

Lourido, Sebastian ;

Shuman, Joel ;

Zhang, Chao ;

Shokat, Kevan M. ;

Hui, Raymond ;

Sibley, L. David .

NATURE, 2010, 465 (7296) :359-U118

[12] Toxoplasmosis [J].

Montoya, JG ;

Liesenfeld, O .

LANCET, 2004, 363 (9425) :1965-1976

[13] Management of Toxoplasma gondii infection during pregnancy [J].

Montoya, Jose G. ;

Remington, Jack S. .

CLINICAL INFECTIOUS DISEASES, 2008, 47 (04) :554-566

[14] Discovery of Potent and Selective Inhibitors of CDPK1 from C. parvum and T. gondii [J].

Murphy, Ryan C. ;

Ojo, Kayode K. ;

Larson, Eric T. ;

Castellanos-Gonzalez, Alejandro ;

Perera, B. Gayani K. ;

Keyloun, Katelyn R. ;

Kim, Jessica E. ;

Bhandari, Janhavi G. ;

Muller, Natascha R. ;

Verlinde, Christophe L. M. J. ;

White, A. Clinton, Jr. ;

Merritt, Ethan A. ;

Van Voorhis, Wesley C. ;

Maly, Dustin J. .

ACS MEDICINAL CHEMISTRY LETTERS, 2010, 1 (07) :331-335

[15] Comparative genomic and phylogenetic analyses of calcium ATPases and calcium-regulated proteins in the apicomplexa [J].

Nagamune, Kisaburo ;

Sibley, L. David .

MOLECULAR BIOLOGY AND EVOLUTION, 2006, 23 (08) :1613-1627

[16] Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors [J].

Ojo, Kayode K. ;

Larson, Eric T. ;

Keyloun, Katelyn R. ;

Castaneda, Lisa J. ;

DeRocher, Amy E. ;

Inampudi, Krishna K. ;

Kim, Jessica E. ;

Arakaki, Tracy L. ;

Murphy, Ryan C. ;

Zhang, Li ;

Napuli, Alberto J. ;

Maly, Dustin J. ;

Verlinde, Christophe L. M. J. ;

Buckner, Frederick S. ;

Parsons, Marilyn ;

Hol, Wim G. J. ;

Merritt, Ethan A. ;

Van Voorhis, Wesley C. .

NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2010, 17 (05) :602-U102

[17] Toxoplasmosis snapshots: Global status of Toxoplasma gondii seroprevalence and implications for pregnancy and congenital toxoplasmosis [J].

Pappas, Georgios ;

Roussos, Nikos ;

Falagas, Matthew E. .

INTERNATIONAL JOURNAL FOR PARASITOLOGY, 2009, 39 (12) :1385-1394

[18]

Schwartzman J.D., 2011, TROPICAL INFECT DIS, P722

[19] Escherichia coli beta-galactosidase as an in vitro and in vivo reporter enzyme and stable transfection marker in the intracellular protozoan parasite Toxoplasma gondii [J].

Seeber, F ;

Boothroyd, JC .

GENE, 1996, 169 (01) :39-45

[20] Toxoplasma gondii in the peripheral blood of patients with acute and chronic toxoplasmosis [J].

Silveira, Claudio ;

Vallochi, Adriana Lima ;

da Silva, Ulisses Rodrigues ;

Muccioli, Cristina ;

Holland, Gary N. ;

Nussenblatt, Robert B. ;

Belfort, Rubens ;

Rizzo, Luiz Vicente .

BRITISH JOURNAL OF OPHTHALMOLOGY, 2011, 95 (03) :396-400

← 1 2 3 →