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The calcium-dependent protein kinase 1 from Toxoplasma gondii as target for structure-based drug design.

ABSTRACT: The apicomplexan protozoan parasites include the causative agents of animal and human diseases ranging from malaria (Plasmodium spp.) to toxoplasmosis (Toxoplasma gondii). The complex life cycle of T. gondii is regulated by a unique family of calcium-dependent protein kinases (CDPKs) that have become the target of intensive efforts to develop new therapeutics. In this review, we will summarize structure-based strategies, recent successes and future directions in the pursuit of specific and selective inhibitors of T. gondii CDPK1.

SUBMITTER: Cardew EM

PROVIDER: S-EPMC5964469 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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The calcium-dependent protein kinase 1 from Toxoplasma gondii as target for structure-based drug design.

Cardew Emily M EM Verlinde Christophe L M J CLMJ Pohl Ehmke E

Parasitology 20171201 2

The apicomplexan protozoan parasites include the causative agents of animal and human diseases ranging from malaria (Plasmodium spp.) to toxoplasmosis (Toxoplasma gondii). The complex life cycle of T. gondii is regulated by a unique family of calcium-dependent protein kinases (CDPKs) that have become the target of intensive efforts to develop new therapeutics. In this review, we will summarize structure-based strategies, recent successes and future directions in the pursuit of specific and selec ...[more]

PMID: 29191253

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Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors.

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Characterisation of the Toxoplasma gondii tyrosine transporter and its phosphorylation by the calcium-dependent protein kinase 3.

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| S-EPMC2168421 | biostudies-literature

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Evaluation of immune responses in mice after DNA immunization with putative Toxoplasma gondii calcium-dependent protein kinase 5.

Project description:Toxoplasma gondii can cause serious public health problems and economic losses worldwide. Calcium-dependent protein kinases (CDPKs) are key mediators of T. gondii signaling pathways and are implicated as important virulence factors. In the present study, we cloned a novel T. gondii CDPK gene, named TgCDPK5, and constructed the eukaryotic expression vector pVAX-CDPK5. Then, we evaluated the immune protection induced by pVAX-CDPK5 in Kunming mice. After injection of pVAX-CDPK5 intramuscularly, immune responses, determined with lymphoproliferative assays and cytokine and antibody measurements, were monitored, and mouse survival times and brain cyst formation were evaluated following challenges with the T. gondii RH strain (genotype I) and the PRU strain (genotype II). pVAX-CDPK5 effectively induced immune responses with increased specific antibodies, a predominance of IgG2a production, and a strong lymphocyte proliferative response. The levels of gamma interferon (IFN-γ), interleukin 2 (IL-2), and IL-12(p70) and the percentages of CD3(+) CD4(+) and CD3(+) CD8(+) cells in mice vaccinated with pVAX-CDPK5 were significantly increased. However, IL-4 and IL-10 were not produced in the vaccinated mice. These results demonstrate that pVAX-CDPK5 can elicit strong humoral and cellular Th1 immune responses. The survival time of immunized mice challenged with the T. gondii RH strain (8.67 ± 4.34 days) was slightly, but not significantly, longer than that in the control groups within 7 days (P > 0.05). The numbers of brain cysts in the mice in the pVAX-CDPK5 group were reduced by ∼40% compared with those in the control groups (P < 0.05), which provides a foundation for the further development of effective subunit vaccines against T. gondii.

| S-EPMC4097438 | biostudies-literature

Toxoplasma gondii cyclic GMP-dependent kinase: chemotherapeutic targeting of an essential parasite protein kinase.

Project description:The trisubstituted pyrrole 4-[2-(4-fluorophenyl)-5-(1-methylpiperidine-4-yl)-1H-pyrrol-3-yl]pyridine (compound 1) has in vivo activity against the apicomplexan parasites Toxoplasma gondii and Eimeria tenella in animal models. The presumptive molecular target of this compound in E. tenella is cyclic GMP-dependent protein kinase (PKG). Native PKG purified from T. gondii has kinetic and pharmacologic properties similar to those of the E. tenella homologue, and both have been functionally expressed as recombinant proteins in T. gondii. Computer modeling of parasite PKG was used to predict catalytic site amino acid residues that interact with compound 1. The recombinant laboratory-generated mutants T. gondii PKG T761Q or T761M and the analogous E. tenella T770 alleles have reduced binding affinity for, and are not inhibited by, compound 1. By all other criteria, PKG with this class of catalytic site substitution is indistinguishable from wild-type enzyme. A genetic disruption of T. gondii PKG can only be achieved if a complementing copy of PKG is provided in trans, arguing that PKG is an essential protein. Strains of T. gondii, disrupted at the genomic PKG locus and dependent upon the T. gondii T761-substituted PKGs, are as virulent as wild type in mice. However, unlike mice infected with wild-type T. gondii that are cured by compound 1, mice infected with the laboratory-generated strains of T. gondii do not respond to treatment. We conclude that PKG represents the primary molecular target responsible for the antiparasitic efficacy of compound 1.

| S-EPMC118020 | biostudies-literature

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