Therapeutic Targets on Toxoplasma gondii Parasite in Combatting Toxoplasmosis

Abdullahi, Sharif Alhassan; Unyah, Ngah Zasmy; Nordin, Noshariza; Basir, Rusliza; Wana, Mohammed Nasir; Ashraf, Ahmad Alapid; Hassan, Yahaya; Mustapha, Tijjani; Majid, Roslaini Abd

doi:10.9734/arrb/2019/v32i230081

Cited by 4 publications

(3 citation statements)

References 88 publications

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“…The secretory organelles (Figure 1), micronemes, rhoptries, and the dense granules, present a sequential system of protein secretion after a proper attachment to a host's cell membrane and initiation of the gliding movement. This is believed to be due to increase in cytosolic calcium through calcium dependent protein kinase (CDPK), a group of kinases that can be use as drug target against T. gondii (Blader, 2009;Muller, 2013;Abdullahi et al, 2019;.…”

Section: Intracellular Growth Replication and Survivalmentioning

confidence: 99%

Intracellular Survival of Toxoplasma gondii: Success and Adaptation

Sharif,

Yahaya

2023

USci

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T. gondii was described as the most successful parasite on earth because of its wide range of host agents, intracellular adaptations and its ability to maintain continuous survival for the life span of its host. Its complex movement, penetration and intracellular replication within the host cell are organized in such a way that it invades and evades immune cells. Formation of parasitoporous vacoule within the host cells and strong anti-oxidant system, are factors that add to its ability to maintain itself in a latent stage, evasion of immune cells attack as well as the effects of reactive oxygen species. In immunocompetent individuals, the infection is asymptomatic, and the parasite exists and persists in a slowly replicating bradyzoite stage in skeletal muscle, heart, brain, retina, and placental tissues. Reactivation of the rapidly replicating tachyzoite stage in settings of immune-depression results with severe consequences. This, therefore, prompts the need to understand certain mechanisms through which this organism succeeds and adapts the harsh condition of host cells during infection. The review further portrays the applicability of diagnostics and therapeutics to diagnose, treat and prevent infection with T. gondii.

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Section: Intracellular Growth Replication and Survivalmentioning

confidence: 99%

Intracellular Survival of Toxoplasma gondii: Success and Adaptation

Sharif,

Yahaya

2023

USci

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“…The current gold-standard treatments, based on a combination of pyrimethamine and sulfonamide, are associated with adverse side effects, mostly pyrimethamine-related bone marrow suppression, intolerance or allergic reactions to the sulfonamide component [22][23][24][25][26][27]. Alternative therapies, such as macrolides, atovaquone, and cotrimoxazole, also have several side effects [28][29][30]. Furthermore, serious and challenging health problems of co-infections of Tg with Mtb have been recorded in some cases, especially in developing countries.…”

Section: Introductionmentioning

confidence: 99%

TZD-Based Hybrid Molecules Act as Dual Anti-Mycobacterium tuberculosis and Anti-Toxoplasma gondii Agents

Dzitko

Kaproń

Paneth

et al. 2023

IJMS

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Two distinct intracellular pathogens, namely Mycobacterium tuberculosis (Mtb) and Toxoplasma gondii (Tg), cause major public health problems worldwide. In addition, serious and challenging health problems of co-infections of Tg with Mtb have been recorded, especially in developing countries. Due to this fact, as well as the frequent cases of resistance to the current drugs, novel anti-infectious therapeutics, especially those with dual (anti-Tg and anti-Mtb) modes of action, are needed. To address this issue, we explored the anti-Tg potential of thiazolidinedione-based (TZD-based) hybrid molecules with proven anti-Mtb potency. Several TZD hybrids with pyridine-4-carbohydrazone (PCH) or thiosemicarbazone (TSC) structural scaffolds were more effective and more selective than sulfadiazine (SDZ) and trimethoprim (TRI). Furthermore, all of these molecules were more selective than pyrimethamine (PYR). Further studies for the most potent TZD-TSC hybrids 7, 8 and 10 and TZD-PCH hybrid molecule 2 proved that these compounds are non-cytotoxic, non-genotoxic and non-hemolytic. Moreover, they could cross the blood–brain barrier (BBB), which is a critical factor linked with ideal anti-Tg drug development. Finally, since a possible link between Tg infection and the risk of glioblastoma has recently been reported, the cytotoxic potential of TZD hybrids against human glioblastoma cells was also evaluated. TZD-PCH hybrid molecule 2 was found to be the most effective, with an IC50 of 19.36 ± 1.13 µg/mL against T98G cells.

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“…Other than CDPKs, the PKG, through cGMP secondary messenger, also functions to facilitate host cell invasion by inducing microneme secretion [8,9]. These functions of CDPKs and many other protein kinases in T. gondii have been reported to be attractive drug targets as they are specific to the parasite and very essential for its survival [10].…”

Section: Introductionmentioning

confidence: 99%

Tinospora crispa Ethanolic Extract Downregulates Protein Kinase Genes Expression and Activity during Toxoplasma gondii Infection: A Prospective Drug Target for Lytic Cycle Inhibition

et al. 2023

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Infection with Toxoplasma gondii remains widespread among humans and animals as water, soil and food continue to serve as the major carriers of the sporulated oocyst. The infection is poorly controlled due to lack of a potent vaccine against the parasite, and the current medication presents severe side effects on the host, less efficacy on the parasite and is accompanied by the potential development of resistance by the parasite. The aim of this study was to evaluate the in vitro activities of ethanolic extract of Tinospora crispa (EETC) on protein kinases involved in the lytic cycle of T. gondii infection in Vero cell line. The EETC was obtained through the maceration of dried stem powder. Vero cells infected with the RH strain of T. gondii were used to evaluate the inhibitory effect of EETC against T. gondii calcium dependent protein kinase (CDPK) genes and microneme proteins (MIC) that are essential for host cell invasion and intracellular replication of the tachyzoite. Gene expression profiling of CDPK genes was determined through quantitative real-time PCR (qPCR) after 24 h of treatment. The expression of microneme protein was determined through western blot technique. The RT-qPCR revealed downregulation of most protein kinase (PK) genes after treatment with EETC. The expression of CDPK1, PKG, CDPK3, CDPK6, CDPK7 genes that participate in the lytic cycle of T. gondii infection was downregulated. The expression of the TgMIC1 and TgMIC2 proteins were observed to have decreased in both 4 and 24 h post-infection treatment models. This study showed that EETC contains promising drug candidates effective against T. gondii that can target the protein kinase genes involved in the lytic cycle of the parasite to prevent disease progression. HIGHLIGHTS This study explored the possible mechanism of action of phytochemicals on Toxoplasma gondii parasite-host cell invasion and intracellular replication The study evaluated the effects of ethanolic extract of Tinospora crispa Miers on protein kinase genes that are involved in host cell invasion The target protein kinase genes were downregulated which prevents the secretion of microneme proteins Inhibition of microneme secretion prevents host cell invasion and intracellular replication by Toxoplasma gondi GRAPHICAL ABSTRACT

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Therapeutic Targets on Toxoplasma gondii Parasite in Combatting Toxoplasmosis

Cited by 4 publications

References 88 publications

Intracellular Survival of Toxoplasma gondii: Success and Adaptation

Intracellular Survival of Toxoplasma gondii: Success and Adaptation

TZD-Based Hybrid Molecules Act as Dual Anti-Mycobacterium tuberculosis and Anti-Toxoplasma gondii Agents

Tinospora crispa Ethanolic Extract Downregulates Protein Kinase Genes Expression and Activity during Toxoplasma gondii Infection: A Prospective Drug Target for Lytic Cycle Inhibition

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