Applying chemical genetic tools to the study of phospho-signalling pathways in malaria parasites

Mitcheson, Deborah; Tobin, Andrew B.; Alam, Mahmood M.

doi:10.1016/j.bbapap.2015.06.014

Cited by 8 publications

(9 citation statements)

References 52 publications

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“…With regard to kinases, it has become clear that they should be included in strategies for antiparasitic drug discovery. A series of recent reviews provides a comprehensive and extensive survey about kinases as rational drug targets not only in eukaryotic pathogens but also in cancer [1][2][3][4].…”

Section: Phosphatases As Essential As Kinases Inmentioning

confidence: 99%

Phosphatases are Emerging as Novel Druggable Targets in Plasmodium

Khalife

Pierrot

2016

Future Microbiol.

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Section: Phosphatases As Essential As Kinases Inmentioning

confidence: 99%

Phosphatases are Emerging as Novel Druggable Targets in Plasmodium

Khalife

Pierrot

2016

Future Microbiol.

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“…Coupled with genetic approaches, comparative omics studies can be used to distinguish “on-target” effects of inhibitors from those resulting from additional/secondary targets. 95 − 97 …”

Section: Opportunity For Polypharmacologymentioning

confidence: 99%

Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities

et al. 2021

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Protein and phosphoinositide kinases have been successfully exploited as drug targets in various disease areas, principally in oncology. In malaria, several protein kinases are under investigation as potential drug targets, and an inhibitor of Plasmodium phosphatidylinositol 4-kinase type III beta (PI4KIIIβ) is currently in phase 2 clinical studies. In this Perspective, we review the potential of kinases as drug targets for the treatment of malaria. Kinases are known to be readily druggable, and many are essential for parasite survival. A key challenge in the design of Plasmodium kinase inhibitors is obtaining selectivity over the corresponding human orthologue(s) and other human kinases due to the highly conserved nature of the shared ATP binding site. Notwithstanding this, there are some notable differences between the Plasmodium and human kinome that may be exploitable. There is also the potential for designed polypharmacology, where several Plasmodium kinases are inhibited by the same drug. Prior to starting the drug discovery process, it is important to carefully assess potential kinase targets to ensure that the inhibition of the desired kinase will kill the parasites in the required life-cycle stages with a sufficiently fast rate of kill. Here, we highlight key target attributes and experimental approaches to consider and summarize the progress that has been made targeting Plasmodium PI4KIIIβ, cGMP-dependent protein kinase, and cyclin-dependent-like kinase 3.

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“…Understanding the relationship between protein kinases, phospho-signaling cascades, and protein substrates is critical for understanding the mechanisms that regulate cellular activity as well as identifying potential therapeutic targets. Identification of G. spinigerum PTMs might become increasingly relevant candidates for the diagnosis, vaccine, and drug development of gnathostomiasis [ 57 , 58 , 59 , 60 ].…”

Section: Future Perspectives Of Proteomics In Improving Diagnosis and Treatment Of Gnathostomiasismentioning

confidence: 99%

Proteomics of Gnathostomiasis: A Way Forward for Diagnosis and Treatment Development

et al. 2021

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Gnathostoma spinigerum is the most common cause of gnathostomiasis in humans. It has a complex life cycle, which requires two intermediate hosts and a definitive host, and poses a high risk for zoonosis. Definitive prognosis of gnathostomiasis relies mainly on the isolation of advanced-stage larvae (aL3), which is very challenging especially if the aL3 is sequestered in difficult-to-reach organs. There is also a lack of a confirmatory diagnostic test for gnathostomiasis. With the ongoing advancement of proteomics, a potential diagnostic approach is underway using immunoproteomics and immunodiagnostics. In addition to this, the employment of mass spectrometry could further elucidate not only understanding the biology of the parasite but also determining potential targets of prospective drugs and vaccines. This article reports the past, present, and future application of proteomics in the study of gnathostomiasis.

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Applying chemical genetic tools to the study of phospho-signalling pathways in malaria parasites

Cited by 8 publications

References 52 publications

Phosphatases are Emerging as Novel Druggable Targets in Plasmodium

Phosphatases are Emerging as Novel Druggable Targets in Plasmodium

Plasmodium Kinases as Potential Drug Targets for Malaria: Challenges and Opportunities

Proteomics of Gnathostomiasis: A Way Forward for Diagnosis and Treatment Development

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