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1. Inhibition of Calcium Dependent Protein Kinase 1 (CDPK1) by Pyrazolopyrimidine Analogs Decreases Establishment and Reoccurrence of Central Nervous System Disease by Toxoplasma gondii

Author

Rutaganira, Florentine U, Barks, Jennifer, Dhason, Mary Savari, Wang, Qiuling, Lopez, Michael S, Long, Shaojun, Radke, Joshua B, Jones, Nathaniel G, Maddirala, Amarendar R, Janetka, James W, Bakkouri, Majida El, Hui, Raymond, Shokat, Kevan M, and Sibley, L David

Subjects
Emerging Infectious Diseases, Foodborne Illness, Vaccine Related, Prevention, Neurosciences, Infectious Diseases, Biodefense, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Animals, Antiprotozoal Agents, Female, Humans, Male, Mice, Protein Kinase Inhibitors, Protein Kinases, Protozoan Proteins, Pyrazoles, Pyrimidines, Structure-Activity Relationship, Toxoplasma, Toxoplasmosis, Cerebral, Medicinal and Biomolecular Chemistry, Organic Chemistry, Pharmacology and Pharmaceutical Sciences, Medicinal & Biomolecular Chemistry
Abstract

Calcium dependent protein kinase 1 (CDPK1) is an essential enzyme in the opportunistic pathogen Toxoplasma gondii. CDPK1 controls multiple processes that are critical to the intracellular replicative cycle of T. gondii including secretion of adhesins, motility, invasion, and egress. Remarkably, CDPK1 contains a small glycine gatekeeper residue in the ATP binding pocket making it sensitive to ATP-competitive inhibitors with bulky substituents that complement this expanded binding pocket. Here we explored structure-activity relationships of a series of pyrazolopyrimidine inhibitors of CDPK1 with the goal of increasing selectivity over host enzymes, improving antiparasite potency, and improving metabolic stability. The resulting lead compound 24 exhibited excellent enzyme inhibition and selectivity for CDPK1 and potently inhibited parasite growth in vitro. Compound 24 was also effective at treating acute toxoplasmosis in the mouse, reducing dissemination to the central nervous system, and decreasing reactivation of chronic infection in severely immunocompromised mice. These findings provide proof of concept for the development of small molecule inhibitors of CDPK1 for treatment of CNS toxoplasmosis.

Published
2017

4. The Cryptosporidium parvum Kinome

Author

Artz, Jennifer D, Wernimont, Amy K, Allali-Hassani, Abdellah, Zhao, Yong, Amani, Mehrnaz, Lin, Yu-Hui, Senisterra, Guillermo, Wasney, Gregory A, Fedorov, Oleg, King, Oliver, Roos, Annette, Lunin, Vlad V, Qiu, Wei, Finerty, Patrick, Hutchinson, Ashley, Chau, Irene, von Delft, Frank, MacKenzie, Farrell, Lew, Jocelyne, Kozieradzki, Ivona, Vedadi, Masoud, Schapira, Matthieu, Zhang, Chao, Shokat, Kevan, Heightman, Tom, and Hui, Raymond

Abstract

Abstract Background Hundreds of millions of people are infected with cryptosporidiosis annually, with immunocompromised individuals suffering debilitating symptoms and children in socioeconomically challenged regions at risk of repeated infections. There is currently no effective drug available. In order to facilitate the pursuit of anti-cryptosporidiosis targets and compounds, our study spans the classification of the Cryptosporidium parvum kinome and the structural and biochemical characterization of representatives from the CDPK family and a MAP kinase. Results The C. parvum kinome comprises over 70 members, some of which may be promising drug targets. These C. parvum protein kinases include members in the AGC, Atypical, CaMK, CK1, CMGC, and TKL groups; however, almost 35% could only be classified as OPK (other protein kinases). In addition, about 25% of the kinases identified did not have any known orthologues outside of Cryptosporidium spp. Comparison of specific kinases with their Plasmodium falciparum and Toxoplasma gondii orthologues revealed some distinct characteristics within the C. parvum kinome, including potential targets and opportunities for drug design. Structural and biochemical analysis of 4 representatives of the CaMK group and a MAP kinase confirms features that may be exploited in inhibitor design. Indeed, screening CpCDPK1 against a library of kinase inhibitors yielded a set of the pyrazolopyrimidine derivatives (PP1-derivatives) with IC50 values of < 10 nM. The binding of a PP1-derivative is further described by an inhibitor-bound crystal structure of CpCDPK1. In addition, structural analysis of CpCDPK4 identified an unprecedented Zn-finger within the CDPK kinase domain that may have implications for its regulation. Conclusions Identification and comparison of the C. parvum protein kinases against other parasitic kinases shows how orthologue- and family-based research can be used to facilitate characterization of promising drug targets and the search for new drugs.

Published
2011

5. Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma

Author

Lourido, Sebastian, Shuman, Joel, Zhang, Chao, Shokat, Kevan M, Hui, Raymond, and Sibley, L David

Subjects
Veterinary Sciences, Agricultural, Veterinary and Food Sciences, Biochemistry and Cell Biology, Biological Sciences, Vaccine Related, Biodefense, Prevention, Emerging Infectious Diseases, Infectious Diseases, Foodborne Illness, 2.2 Factors relating to the physical environment, Aetiology, Infection, Amino Acid Sequence, Cells, Cultured, Exocytosis, Fibroblasts, Foreskin, Gene Knockout Techniques, Host-Pathogen Interactions, Humans, Male, Molecular Sequence Data, Organelles, Phenotype, Protein Kinases, Protein Phosphatase 1, Toxoplasma, General Science & Technology
Abstract

Calcium-regulated exocytosis is a ubiquitous process in eukaryotes, whereby secretory vesicles fuse with the plasma membrane and release their contents in response to an intracellular calcium surge. This process regulates various cellular functions such as plasma membrane repair in plants and animals, the discharge of defensive spikes in Paramecium, and the secretion of insulin from pancreatic cells, immune modulators from lymphocytes, and chemical transmitters from neurons. In animal cells, serine/threonine kinases including cAMP-dependent protein kinase, protein kinase C and calmodulin kinases have been implicated in calcium-signal transduction leading to regulated secretion. Although plants and protozoa also regulate secretion by means of intracellular calcium, the method by which these signals are relayed has not been explained. Here we show that the Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) is an essential regulator of calcium-dependent exocytosis in this opportunistic human pathogen. Conditional suppression of TgCDPK1 revealed that it controls calcium-dependent secretion of specialized organelles called micronemes, resulting in a block of essential phenotypes including parasite motility, host-cell invasion, and egress. These phenotypes were recapitulated by using a chemical biology approach in which pyrazolopyrimidine-derived compounds specifically inhibited TgCDPK1 and disrupted the parasite's life cycle at stages dependent on microneme secretion. Inhibition was specific to TgCDPK1, because expression of a resistant mutant kinase reversed sensitivity to the inhibitor. TgCDPK1 is conserved among apicomplexans and belongs to a family of kinases shared with plants and ciliates, suggesting that related CDPKs may have a function in calcium-regulated secretion in other organisms. Because this kinase family is absent from mammalian hosts, it represents a validated target that may be exploitable for chemotherapy against T. gondii and related apicomplexans.

Published
2010

8. Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial

Author

Hung, Ivan Fan-Ngai, Zhang, Anna Jinxia, To, Kelvin Kai-Wang, Chan, Jasper Fuk-Woo, Li, Patrick, Wong, Tin-Lun, Zhang, Ricky, Chan, Tuen-Ching, Chan, Brian Chun-Yuan, Wai, Harrison Ho, Chan, Lok-Wun, Fong, Hugo Pak-Yiu, Hui, Raymond Kar-Ching, Kong, Ka-Lun, Leung, Arthur Chun-Fung, Ngan, Abe Ho-Ting, Tsang, Louise Wing-Ki, Yeung, Alex Pat-Chung, Yiu, Geo Chi-Ngo, Yung, Wing, Lau, Johnson Y-N, Chen, Honglin, Chan, Kwok-Hung, and Yuen, Kwok-Yung

Published
2016
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9. Structural basis for species-selective targeting of Hsp90 in a pathogenic fungus

Author

Whitesell, Luke, Robbins, Nicole, Huang, David S., McLellan, Catherine A., Shekhar-Guturja, Tanvi, LeBlanc, Emmanuelle V., Nation, Catherine S., Hui, Raymond, Hutchinson, Ashley, Collins, Cathy, Chatterjee, Sharanya, Trilles, Richard, Xie, Jinglin L., Krysan, Damian J., Lindquist, Susan, Porco, Jr., John A., Tatu, Utpal, Brown, Lauren E., Pizarro, Juan, and Cowen, Leah E.

Published
2019
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10. Cost-utility analysis of sacituzumab govitecan versus chemotherapy for the treatment of metastatic triple-negative breast cancer in Singapore.

Author

Cher, Boon Piang, Goh, Sharon, Aziz, Mohamed Ismail Abdul, Wong, Grace, Ng Chee Hui, Raymond, Ong, Benjamin Shao-Kiat, and Ng, Kwong-Hoe

Abstract

To assess the cost-effectiveness of sacituzumab govitecan for treating relapsed or refractory metastatic triple-negative breast cancer (TNBC) in Singapore. A three-state partitioned survival model was developed to evaluate the cost-effectiveness of sacituzumab govitecan from a healthcare system perspective over 5 years. Clinical inputs were obtained from the ASCENT trial. Health state utilities were retrieved from the literature and direct costs were sourced from public healthcare institutions in Singapore. Sensitivity and scenario analyses were conducted to explore the impact of uncertainties and assumptions on cost-effectiveness results. Compared with single-agent chemotherapy, sacituzumab govitecan was associated with a base-case incremental cost-effectiveness ratio (ICER) of S$328,000 (US$237,816) per quality-adjusted life year (QALY) gained. One-way sensitivity analyses showed that the ICER was most sensitive to the cost of sacituzumab govitecan and progression-free utility values. Regardless of variation in these parameters, the ICER remained high, and a substantial price reduction was required to reduce the ICER. At its current price, sacituzumab govitecan does not represent a cost-effective treatment for relapsed or refractory metastatic TNBC in Singapore. Our findings will be useful to inform funding decisions alongside other factors including clinical effectiveness, safety, and budget impact considerations. [ABSTRACT FROM AUTHOR]

Published
2024
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19. A potent series targeting the malarial cGMP-dependent protein kinase clears infection and blocks transmission

Author

Baker, David A., Stewart, Lindsay B., Large, Jonathan M., Bowyer, Paul W., Ansell, Keith H., Jiménez-Díaz, María B., El Bakkouri, Majida, Birchall, Kristian, Dechering, Koen J., Bouloc, Nathalie S., Coombs, Peter J., Whalley, David, Harding, Denise J., Smiljanic-Hurley, Ela, Wheldon, Mary C., Walker, Eloise M., Dessens, Johannes T., Lafuente, María José, Sanz, Laura M., Gamo, Francisco-Javier, Ferrer, Santiago B., Hui, Raymond, Bousema, Teun, Angulo-Barturén, Iñigo, Merritt, Andy T., Croft, Simon L., Gutteridge, Winston E., Kettleborough, Catherine A., and Osborne, Simon A.

Published
2017
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27. Structures of the cGMP-dependent protein kinase in malaria parasites reveal a unique structural relay mechanism for activation

Author

El Bakkouri, Majida, Kouidmi, Imène, Wernimont, Amy K., Amani, Mehrnaz, Hutchinson, Ashley, Loppnau, Peter, Kim, Jeong Joo, Flueck, Christian, Walker, John R., Seitova, Alma, Senisterra, Guillermo, Kakihara, Yoshito, Kim, Choel, Blackman, Michael J., Calmettes, Charles, Baker, David A., Hui, Raymond, University of Toronto, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Baylor College of Medicine (BCM), Baylor University, London School of Hygiene and Tropical Medicine (LSHTM), The Francis Crick Institute [London], Toronto General Hospital Research Institute [Canada] (TGHRI), The Structural Genomics Consortium is a registered charity (no. 1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada through the Ontario Genomics Institute (OGI-055), GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda, and the Wellcome Trust. This work was also supported by Wellcome Trust Grants 092809/Z/10/Z, 106240/Z/14/Z and 106239/Z/14/A (to D.A.B. and M.J.B.). This work was also supported by the Francis Crick Institute (M.J.B.) , which receives its core funding from Cancer Research UK Grant FC001043, UK Medical Research Council Grant FC001043, and Wellcome Trust Grant FC001043. C.C. is the recipient of Fonds de Recherche Québec–Santé (FRQS) Research Scholar Junior 1 Career Award 251848, supported by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant RGPIN-2017-06091, Fonds de Recherche Québec–Nature et Technologies (FRQNT) Grant 2019-NC-253753, as well as with instrumentation and infrastructure support provided by the Armand–Frappier Foundation. This research used resources of the Canadian Light Source at Beamline 08ID-1, which is supported by the Canada Foundation for Innovation, Natural Sciences and Engineering Research Council of Canada, and Canadian Institutes of Health Research, and and of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357.

Subjects
Plasmodium, Medical Sciences, Binding Sites, Protein Conformation, [SDV]Life Sciences [q-bio], Plasmodium falciparum, malaria, Biological Sciences, Crystallography, X-Ray, Kinetics, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, PNAS Plus, cyclic GMP, Catalytic Domain, cardiovascular system, Cyclic GMP-Dependent Protein Kinases, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, structure, Amino Acid Sequence, signal transduction, Protein Binding
Abstract

Significance Despite being one of the first protein kinases discovered, cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) has not been successfully crystallized previously, leaving many unanswered questions about its mechanism of activation. We report herein the structure of cGMP-free PKG from Plasmodium parasites, the causative agents of malaria, one of the world’s deadliest infectious diseases. The structures, combined with data from biochemical and biophysical experiments, provide insight into a mechanism of activation that involves previously unpredicted interdomain communication via a structural relay system. In addition to the full structure of PKG, our work contributes important functional information for a key antimalarial drug target., The cyclic guanosine-3′,5′-monophosphate (cGMP)-dependent protein kinase (PKG) was identified >25 y ago; however, efforts to obtain a structure of the entire PKG enzyme or catalytic domain from any species have failed. In malaria parasites, cooperative activation of PKG triggers crucial developmental transitions throughout the complex life cycle. We have determined the cGMP-free crystallographic structures of PKG from Plasmodium falciparum and Plasmodium vivax, revealing how key structural components, including an N-terminal autoinhibitory segment (AIS), four predicted cyclic nucleotide-binding domains (CNBs), and a kinase domain (KD), are arranged when the enzyme is inactive. The four CNBs and the KD are in a pentagonal configuration, with the AIS docked in the substrate site of the KD in a swapped-domain dimeric arrangement. We show that although the protein is predominantly a monomer (the dimer is unlikely to be representative of the physiological form), the binding of the AIS is necessary to keep Plasmodium PKG inactive. A major feature is a helix serving the dual role of the N-terminal helix of the KD as well as the capping helix of the neighboring CNB. A network of connecting helices between neighboring CNBs contributes to maintaining the kinase in its inactive conformation. We propose a scheme in which cooperative binding of cGMP, beginning at the CNB closest to the KD, transmits conformational changes around the pentagonal molecule in a structural relay mechanism, enabling PKG to orchestrate rapid, highly regulated developmental switches in response to dynamic modulation of cGMP levels in the parasite.

Published
2019
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29. Multi-Center Evaluation of Artificial Intelligent Imaging And Clinical Models For Predicting Neoadjuvant Chemotherapy Response In Breast Cancer

Author

Qi, Tan Hong, primary, Hian, Ong Hiok, additional, Kumaran, Arjunan Muthu, additional, Tan, Tira J., additional, Cong, Ryan Shea Tan Ying, additional, Su-Xin, Ghislaine Lee, additional, Hsuen, Elaine Lim, additional, Hui, Raymond Ng Chee, additional, Chert, Richard Yeo Ming, additional, Tching, Faye Lynette Lim Wei, additional, Zewen, Zhang, additional, Hui, Christina Yang Shi, additional, Xin, Wong Ru, additional, Kai, Gideon Ooi Su, additional, Hao, Lester Leong Chee, additional, Ming, Tan Su, additional, Preetha, Madhukumar, additional, Yirong, Sim, additional, Mien, Veronique Tan Kiak, additional, Yeong, Joe, additional, Yong, Wong Fuh, additional, Yiyu, Cai, additional, and Nei, Wen Long, additional

Published
2021
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32. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

Author

Frearson, Julie A., Brand, Stephen, McElroy, Stuart P., Cleghorn, Laura A.T., Smid, Ondrej, Stojanovski, Laste, Price, Helen P., Guther, M. Lucia S., Torrie, Leah S., Robinson, David A., Hallyburton, Irene, Mpamhanga, Chidochangu P., Brannigan, James A., Wilkinson, Anthony J., Hodgkinson, Michael, Hui, Raymond, Qiu, Wei, Raimi, Olawale G., van Aalten, Daan M.F., Brenk, Ruth, Gilbert, Ian H., Read, Kevin D., Fairlamb, Alan H., Ferguson, Michael A.J., Smith, Deborah F., and Wyatt, Paul G.

Subjects
Control, Care and treatment, Usage, Physiological aspects, Genetic aspects, Research, Health aspects, Transferases -- Physiological aspects -- Control -- Research, Post-translational modifications -- Research, Trypanosomiasis -- Genetic aspects -- Care and treatment -- Research, Enzyme inhibitors -- Usage -- Health aspects, Post-translational modification -- Research
Abstract

Protein N-myristoylation is a ubiquitous eukaryotic co- and posttranslational modification and is required for the membrane targeting and biological activity of many important proteins (1,2). The N-myristoylation reaction--the transfer of [...], African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma bruceispp., is responsible for ~30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target--T. brucei N-myristoyltransferase--leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis.

Published
2010
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35. Genome-scale protein expression and structural biology of Plasmodium falciparum and related Apicomplexan organisms

Author

Vedadi, Masoud, Lew, Jocelyne, Artz, Jennifer, Amani, Mehrnaz, Zhao, Yong, Dong, Aiping, Wasney, Gregory A., Gao, Mian, Hills, Tanya, Brokx, Stephen, Qiu, Wei, Sharma, Sujata, Diassiti, Angelina, Alam, Zahoor, Melone, Michelle, Mulichak, Anne, Wernimont, Amy, Bray, James, Loppnau, Peter, Plotnikova, Olga, Newberry, Kate, Sundararajan, Emayavaram, Houston, Simon, Walker, John, Tempel, Wolfram, Bochkarev, Alexey, Kozieradzki, Ivona, Edwards, Aled, Arrowsmith, Cheryl, Roos, David, Kain, Kevin, and Hui, Raymond

Published
2007
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38. Screening for ligands using a generic and high-throughput light-scattering-based assay

Author

Senisterra, Guillermo A., Markin, Eugene, Yamazaki, Ken, Hui, Raymond, Vedadi, Masoud, and Awrey, Donald E.

Subjects
Usage, Research, Methods, Health screening -- Methods -- Research -- Usage, Generic drugs -- Usage -- Research, Light scattering -- Research -- Methods -- Usage, Bioassay -- Research -- Usage -- Methods, Protein synthesis -- Research -- Usage -- Methods, Biological assay -- Research -- Usage -- Methods, Protein biosynthesis -- Research -- Usage -- Methods, Medical screening -- Methods -- Research -- Usage
Abstract

Rapid identification of small molecules that interact with protein targets using a generic screening method greatly facilitates the development of therapeutic agents. The authors describe a novel method for performing [...]

Published
2006

43. Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

Author

Vu, Hoan, Pedro, Liliana, Mak, Tin, McCormick, Brendan, Rowley, Jessica, Liu, Miaomiao, Di Capua, Angela, Williams-Noonan, Billy, Pham, Ngoc B., Pouwer, Rebecca, Nguyen, Bao, Andrews, Katherine T., Skinner-Adams, Tina, Kim, Jessica, Hol, Wim G. J., Hui, Raymond, Crowther, Gregory J., Van Voorhis, Wesley C., and Quinn, Ronald J.

Subjects
Antimalarials, Biological Products, natural products, native mass spectrometry, target identification, fragments, Plasmodium falciparum, malaria, Drug Evaluation, Preclinical, Protozoan Proteins, Featured Article, Mass Spectrometry, Protein Binding
Abstract

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.

Published
2018

45. Producing Proteins

Author

Edwards, Aled, primary, Arrowsmith, Cheryl, additional, Hui, Raymond, additional, Marino, Fabien, additional, Savchenko, Alexei, additional, Yamazaki, Ken, additional, and Yee, Adelinda, additional

Published
2003
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48. Robotics research at Canadian Space Agency

Author

Hui, Raymond

Subjects
Cybernetics
Abstract

In addition to major crown projects such as the Mobile Servicing System for Space Station, the Canadian Space Agency is also engaged in internal, industrial and academic research and development activities in robotics and other space-related areas of science and technology. These activities support current and future space projects, and lead to technology development which can be spun off to terrestrial applications, thus satisfying the Agency's objective of providing economic benefits to the public at large through its space-related work.

Published
1994

50. Identification of Small Molecule Inhibitors That Block the Toxoplasma gondii Rhoptry Kinase ROP18

Author

Tang, Keliang, Stashko, Michael, Hui, Raymond, Janzen, William, Schapira, Matthieu, Sibley, L. David, Jones, Nathaniel G., Simpson, Catherine, and Kireev, Dmitri

Abstract

The protozoan parasite Toxoplasma gondii secretes a family of serine-threonine protein kinases into its host cell in order to disrupt signaling and alter immune responses. One prominent secretory effector is the rhoptry protein 18 (ROP18), a serine-threonine kinase that phosphorylates immunity related GTPases (IRGs) and hence blocks interferon gamma-mediated responses in rodent cells. Previous genetic studies show that ROP18 is a major virulence component of T. gondii strains from North and South America. Here, we implemented a high throughput screen to identify small molecule inhibitors of ROP18 in vitro and subsequently validated their specificity within infected cells. Although ROP18 was not susceptible to many kinase-directed inhibitors that affect mammalian kinases, the screen identified several sub micromolar inhibitors that belong to three chemical scaffolds: oxindoles, 6-azaquinazolines, and pyrazolopyridines. Treatment of interferon gamma-activated cells with one of these inhibitors enhanced immunity related GTPase recruitment to wild type parasites, recapitulating the defect of Δ rop18 mutant parasites, consistent with targeting ROP18 within infected cells. These compounds provide useful starting points for chemical biology experiments or as leads for therapeutic interventions designed to reduce parasite virulence.

Published
2016
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