The calcium-dependent protein kinase 1 from <i>Toxoplasma gondii</i> as target for structure-based drug design

Cardew, Emily; Verlinde, Christophe L. M. J.; Pohl, Ehmke

doi:10.1017/s0031182017001901

Cited by 27 publications

(19 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Antiparasitic drug development based on targeting protein kinase enzymes is a well-established approach (17). Calciumdependent protein kinase 1 (CDPK1) represents a promising drug target, as CDPK1 is likely descended from the plant lineage of T. gondii and thus is absent from mammalian hosts (18)(19)(20)(21). CDPK1 activity is essential for microneme secretion, host cell invasion, and egress of T. gondii (18,22,23) and can be selectively targeted by a class of ATP-competitive compounds, collectively named bumped kinase inhibitors (BKIs).…”

mentioning

confidence: 99%

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Sánchez-Sánchez

Ferre

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Previous studies on drug efficacy showed low protection against abortion and vertical transmission of Toxoplasma gondii in pregnant sheep. Bumped kinase inhibitors (BKIs), which are ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1), were shown to be highly efficacious against several apicomplexan parasites in vitro and in laboratory animal models. Here, we present the safety and efficacy of BKI-1294 treatment (dosed orally at 100 mg/kg of body weight 5 times every 48 h) initiated 48 h after oral infection of sheep at midpregnancy with 1,000 TgShSp1 oocysts. BKI-1294 demonstrated systemic exposure in pregnant ewes, with maximum plasma concentrations of 2 to 3 M and trough concentrations of 0.4 M at 48 h after each dose. Oral administration of BKI-1294 in uninfected sheep at midpregnancy was deemed safe, since there were no changes in behavior, fecal consistency, rectal temperatures, hematological and biochemical parameters, or fetal mortality/morbidity. In ewes infected with a T. gondii oocyst dose lethal for fetuses, BKI-1294 treatment led to a minor rectal temperature increase after infection and a decrease in fetal/lamb mortality of 71%. None of the lambs born alive in the treated group exhibited congenital encephalitis lesions, and vertical transmission was prevented in 53% of them. BKI-1294 treatment during infection led to strong interferon gamma production after cell stimulation in vitro and a low humoral immune response to soluble tachyzoite antigens but high levels of anti-SAG1 antibodies. The results demonstrate a proof of concept for the therapeutic use of BKI-1294 to protect ovine fetuses from T. gondii infection during pregnancy.

show abstract

mentioning

confidence: 99%

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Sánchez-Sánchez

Ferre

et al. 2019

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…For example, Nolatrexed, an anticancer drug was discovered using the structure of E. coli thymidylate synthase (46% sequence identity with human homolog) [87]. Kinase inhibitors to kill the Plasmodium falciparum were identified using structures of protein kinases from Cryptosporidium and Toxoplasma (61 and 74% sequence identity, respectively) [88].…”

Section: Three-dimensional Structuresmentioning

confidence: 99%

Questing functions and structures of hypothetical proteins from Campylobacter jejuni: a computer-aided approach

et al. 2020

View full text Add to dashboard Cite

Campylobacter jejuni (C. jejuni) is considered to be one of the most frequent causes of bacterial gastroenteritis globally, especially in young children. The genome of C. jejuni contains many proteins with unknown functions termed as hypothetical proteins (HPs). These proteins might have essential biological role to show the full spectrum of this bacterium. Hence, our study aimed to determine the functions of HPs, pertaining to the genome of C. jejuni. An in-silico work flow integrating various tools were performed for functional assignment, three-dimensional structure determination, domain architecture predictors, subcellular localization, physicochemical characterization, and protein–protein interactions (PPIs). Sequences of 267 HPs of C. jejuni were analyzed and successfully attributed the function of 49 HPs with higher confidence. Here, we found proteins with enzymatic activity, transporters, binding and regulatory proteins as well as proteins with biotechnological interest. Assessment of the performance of various tools used in this analysis revealed an accuracy of 95% using receiver operating characteristic (ROC) curve analysis. Functional and structural predictions and the results from ROC analyses provided the validity of in-silico tools used in the present study. The approach used for this analysis leads us to assign the function of unknown proteins and relate them with the functions that have already been described in previous literature.

show abstract

“…CDPKs represent attractive drug targets because of their absence from the mammalian genome [20]. Several recent screens have targeted CDPKs for the development of new antiparasitic compounds [85–87]. …”

Section: Ca2+-dependent Protein Kinasesmentioning

confidence: 99%

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Triana

Márquez-Nogueras

Vella

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

View full text Add to dashboard Cite

Toxoplasma gondii has a complex life cycle involving different hosts and is dependent on fast responses, as the parasite reacts to changing environmental conditions. T. gondii causes disease by lysing the host cells that it infects and it does this by reiterating its lytic cycle, which consists of host cell invasion, replication inside the host cell, and egress causing host cell lysis. Calcium ion (Ca2+) signaling triggers activation of molecules involved in the stimulation and enhancement of each step of the parasite lytic cycle. Ca2+ signaling is essential for the cellular and developmental changes that support T. gondii parasitism. The characterization of the molecular players and pathways directly activated by Ca2+ signaling in Toxoplasma is sketchy and incomplete. The evolutionary distance between Toxoplasma and other eukaryotic model systems makes the comparison sometimes not informative. The advent of new genomic information and new genetic tools applicable for studying Toxoplasma biology is rapidly changing this scenario. The Toxoplasma genome reveals the presence of many genes potentially involved in Ca2+ signaling, even though the role of most of them is not known. The use of Genetically Encoded Calcium Indicators (GECIs) has allowed studies on the role of novel calcium-related proteins on egress, an essential step for the virulence and dissemination of Toxoplasma. In addition, the discovery of new Ca2+ players is generating novel targets for drugs, vaccines, and diagnostic tools and a better understanding of the biology of these parasites.

show abstract

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

Cited by 27 publications

References 58 publications

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Treatment with Bumped Kinase Inhibitor 1294 Is Safe and Leads to Significant Protection against Abortion and Vertical Transmission in Sheep Experimentally Infected with Toxoplasma gondii during Pregnancy

Questing functions and structures of hypothetical proteins from Campylobacter jejuni: a computer-aided approach

Calcium signaling and the lytic cycle of the Apicomplexan parasite Toxoplasma gondii

Contact Info

Product

Resources

About