A Specific Inhibitor of PfCDPK4 Blocks Malaria Transmission: Chemical-genetic Validation

被引：80

作者：

Ojo, Kayode K. ^{[1
]}

Eastman, Richard T. ^{[2
]}

Vidadala, RamaSubbaRao ^{[3
]}

Zhang, Zhongsheng ^{[4
]}

Rivas, Kasey L. ^{[1
]}

Choi, Ryan ^{[1
]}

Lutz, Justin D. ^{[5
]}

Reid, Molly C. ^{[1
]}

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

Hulverson, Matthew A. ^{[1
]}

Kennedy, Mark ^{[6
]}

Isoherranen, Nina ^{[5
]}

Kim, Laura M. ^{[7
]}

Comess, Kenneth M. ^{[7
]}

Kempf, Dale J. ^{[7
]}

Verlinde, Christophe L. M. J. ^{[4
]}

Su, Xin-zhuan ^{[2
]}

Kappe, Stefan H. I. ^{[5
]}

Maly, Dustin J. ^{[3
]}

Fan, Erkang ^{[4
]}

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

机构：

[1] Univ Washington, Dept Med, Div Allergy & Infect Dis, Seattle, WA 98195 USA

[2] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA

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

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

[5] Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA

[6] Seattle Biomed Res Inst, Washington, DC USA

[7] AbbVie, Global Pharmaceut R&D, N Chicago, IL USA

来源：

JOURNAL OF INFECTIOUS DISEASES | 2014年 / 209卷 / 02期

基金：

美国国家卫生研究院;

关键词：

Plasmodium falciparum; malaria transmission-blocking; calcium-dependent protein kinase 4; bumped kinase inhibitors; PROTEIN-KINASE; 1; CALCIUM; POTENT; EXPRESSION; RESISTANCE; PRIMAQUINE; MOSQUITOS; PARASITES;

D O I：

10.1093/infdis/jit522

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Malaria parasites are transmitted by mosquitoes, and blocking parasite transmission is critical in reducing or eliminating malaria in endemic regions. Here, we report the pharmacological characterization of a new class of malaria transmission-blocking compounds that acts via the inhibition of Plasmodia CDPK4 enzyme. We demonstrate that these compounds achieved selectivity over mammalian kinases by capitalizing on a small serine gatekeeper residue in the active site of the Plasmodium CDPK4 enzyme. To directly confirm the mechanism of action of these compounds, we generated P. falciparum parasites that express a drug-resistant methionine gatekeeper (S147M) CDPK4 mutant. Mutant parasites showed a shift in exflagellation EC50 relative to the wild-type strains in the presence of compound 1294, providing chemical-genetic evidence that CDPK4 is the target of the compound. Pharmacokinetic analyses suggest that coformulation of this transmission-blocking agent with asexual stage antimalarials such as artemisinin combination therapy (ACT) is a promising option for drug delivery that may reduce transmission of malaria including drug-resistant strains. Ongoing studies include refining the compounds to improve efficacy and toxicological properties for efficient blocking of malaria transmission.

引用

页码：275 / 284

页数：10

共 29 条

[1] Quantitative assessment of Plasmodium falciparum sexual development reveals potent transmission-blocking activity by methylene blue [J].

Adjalley, Sophie H. ;

Johnston, Geoffrey L. ;

Li, Tao ;

Eastman, Richard T. ;

Ekland, Eric H. ;

Eappen, Abraham G. ;

Richman, Adam ;

Sim, B. Kim Lee ;

Lee, Marcus C. S. ;

Hoffman, Stephen L. ;

Fidock, David A. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (47) :E1214-E1223

[2] A set of independent selectable markers for transfection of the human malaria parasite Plasmodium falciparum [J].

Ben Mamoun, C ;

Gluzman, IY ;

Goyard, S ;

Beverley, SM ;

Goldberg, DE .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (15) :8716-8720

[3] Calcium and a calcium-dependent protein kinase regulate gamete formation and mosquito transmission in a malaria parasite [J].

Billker, O ;

Dechamps, S ;

Tewari, R ;

Wenig, G ;

Franke-Fayard, B ;

Brinkmann, V .

CELL, 2004, 117 (04) :503-514

[4] Revisiting the circulation time of Plasmodium falciparum gametocytes: molecular detection methods to estimate the duration of gametocyte carriage and the effect of gametocytocidal drugs [J].

Bousema, Teun ;

Okell, Lucy ;

Shekalaghe, Seif ;

Griffin, Jamie T. ;

Omar, Sabah ;

Sawa, Patrick ;

Sutherland, Colin ;

Sauerwein, Robert ;

Ghani, Azra C. ;

Drakeley, Chris .

MALARIA JOURNAL, 2010, 9 :136

[5] Reducing safety-related drug attrition: the use of in vitro pharmacological profiling [J].

Bowes, Joanne ;

Brown, Andrew J. ;

Hamon, Jacques ;

Jarolimek, Wolfgang ;

Sridhar, Arun ;

Waldron, Gareth ;

Whitebread, Steven .

NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (12) :909-922

[6] Comparison of Human Ether-a-go-go Related Gene Screening Assays Based on IonWorks Quattro and Thallium Flux [J].

Bridal, Terry R. ;

Margulis, Michael ;

Wang, Xin ;

Donio, Michael ;

Sorota, Steve .

ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES, 2010, 8 (06) :755-765

[7] Stable transgene expression in Plasmodium falciparum [J].

Crabb, BS ;

Triglia, T ;

Waterkeyn, JG ;

Cowman, AF .

MOLECULAR AND BIOCHEMICAL PARASITOLOGY, 1997, 90 (01) :131-144

[8] Transformation of malaria parasites by the spontaneous uptake and expression of DNA from human erythrocytes [J].

Deitsch, KW ;

Driskill, CL ;

Wellems, TE .

NUCLEIC ACIDS RESEARCH, 2001, 29 (03) :850-853

[9] Protein kinases as targets for antimalarial intervention: Kinomics, structure-based design, transmission-blockade, and targeting host cell enzymes [J].

Doerig, C ;

Billker, O ;

Pratt, D ;

Endicott, J .

BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS, 2005, 1754 (1-2) :132-150

[10] Artemisinin resistance: current status and scenarios for containment [J].

Dondorp, Arjen M. ;

Yeung, Shunmay ;

White, Lisa ;

Nguon, Chea ;

Day, Nicholas P. J. ;

Socheat, Duong ;

von Seidlein, Lorenz .

NATURE REVIEWS MICROBIOLOGY, 2010, 8 (04) :272-280

← 1 2 3 →