Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia

Kesely, Kristina R.; Noomuna, Panae; Vieth, Michał; Hipskind, Philip A.; Haldar, Kasturi; Pantaleo, Antonella; Turrini, Francesco Michelangelo

doi:10.1371/journal.pone.0242372

Cited by 15 publications

(20 citation statements)

References 59 publications

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“…The mechanism for these effects is likely to include PTP inhibition, phosphorylation of Y8, and binding of the cytoplasmic domain to an SH2 domain on the membrane domain (386). Further work is needed to understand the many different physiological, pathophysiological, and pharmacological conditions affecting the tyrosine phosphorylation status of band 3 (362,(473)(474)(475)(476)(477)(478)(479).…”

Section: Role Of Cytoplasmic Domain and Oxidative Stress In Transportmentioning

confidence: 99%

Cell physiology and molecular mechanism of anion transport by erythrocyte band 3/AE1

Jennings

2021

American Journal of Physiology-Cell Physiology

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The major transmembrane protein of the red blood cell, known as band 3, AE1, and SLC4A1, has two main functions: 1) catalysis of Cl-/HCO3- exchange, one of the steps in CO2 excretion; 2) anchoring the membrane skeleton. This review summarizes the 150 year history of research on red cell anion transport and band 3 as an experimental system for studying membrane protein structure and ion transport mechanisms. Important early findings were that red cell Cl- transport is a tightly coupled 1:1 exchange and band 3 is labeled by stilbenesulfonate derivatives that inhibit anion transport. Biochemical studies showed that the protein is dimeric or tetrameric (paired dimers) and that there is one stilbenedisulfonate binding site per subunit of the dimer. Transport kinetics and inhibitor characteristics supported the idea that the transporter acts by an alternating access mechanism with intrinsic asymmetry. The sequence of band 3 cDNA provided a framework for detailed study of protein topology and amino acid residues important for transport. The identification of genetic variants produced insights into the roles of band 3 in red cell abnormalities and distal renal tubular acidosis. The publication of the membrane domain crystal structure made it possible to propose concrete molecular models of transport. Future research directions include improving our understanding of the transport mechanism at the molecular level and of the integrative relationships among band 3, hemoglobin, carbonic anhydrase, and gradients (both transmembrane and subcellular) of HCO3-, Cl-, O2, CO2, pH, and NO metabolites during pulmonary and systemic capillary gas exchange.

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Section: Role Of Cytoplasmic Domain and Oxidative Stress In Transportmentioning

confidence: 99%

Cell physiology and molecular mechanism of anion transport by erythrocyte band 3/AE1

Jennings

2021

American Journal of Physiology-Cell Physiology

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“…This calls for the development of next-generation drugs with (i) untapped modes of action to prevent cross-resistance and (ii) have low propensity for the emergence of de novo resistance. In recent years P. falciparum has been shown to require the activity of several of its host kinases 31,45,46 , which when inhibited chemically, result in parasite death. This suggests that host targeted drug discovery (HDT) may be feasible avenue for malaria treatments as it has for other infectious diseases (reviewed in 47 ).…”

Section: Resultsmentioning

confidence: 99%

Network analysis of large phospho-signalling datasets: application to Plasmodium-erythrocyte interactions

Adderley

O'Donoghue

Doerig

et al. 2021

Preprint

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Phosphorylation based signalling is a complicated and intertwined series of pathways critical to all domains of life. This interconnectivity, though essential to life, makes understanding and decoding the interactions difficult. Large datasets of phosphorylation interactions through the activity of kinases on their numerous effectors are now being generated, however interpretation of the network environment remains challenging. In humans, many phosphorylation interactions have been identified across published works to form the known phosphorylation interaction network. We overlayed phosphorylation datasets onto this network which provided information to each of the connections. To analyse the datasets now mapped into a network, we designed a pathway analysis that uses random walks to identify chains of phosphorylation events occurring much more or much less frequently than expected. This analysis highlights pathways of phosphorylation that work synergistically, providing a rapid interpretation of the most critical pathways in a given dataset. Here we used datasets of human red blood cells infected with the notable stages of Plasmodium falciparum asexual development. The analysis identified several known signalling interactions, and additional interactions which could form the basis of numerous future studies. The network analysis designed here is widely applicable to any comparative phosphorylation dataset across infection and disease and can provide a rapid and reliable analysis to guide validation studies.

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“…This calls for the development of next-generation drugs with (i) untapped modes of action to prevent cross-resistance and (ii) have low propensity for the emergence of de novo resistance. In recent years P. falciparum has been shown to require the activity of several of its host kinases 30,44,45 , which when inhibited chemically, result in parasite death. This suggests that host targeted drug discovery (HDT) may be feasible avenue for malaria treatments as it has for other infectious diseases (reviewed in 46 ).…”

Section: Discussionmentioning

confidence: 99%

MAPPINGS v1.0, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

Adderley

O'Donoghue

Davis

et al. 2021

Preprint

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Phosphorylation-based signalling implicates a complex and intertwined series of pathways and is critical to all domains of life. The interconnectivity between pathways results in the emergence of complex networks whose elucidation present a serious challenge. Large datasets of phosphorylation interactions through the activity of kinases on their numerous substrates are constantly being generated, however deciphering the complex network structure hidden in these datasets remains challenging. Many phosphorylation interactions occurring in human cells have been identified and constitute the basis for the known phosphorylation interaction network. We overlayed onto this network phosphorylation datasets obtained from an antibody microarray approach aimed at determining changes in phospho-signalling of host erythrocytes to infection with the malaria parasite Plasmodium falciparum. To analyse the datasets now mapped into the interaction network, we designed a pathway analysis tool denoted MAPPINGS that uses random walks to identify chains of phosphorylation events occurring much more or much less frequently than expected. MAPPINGS highlights pathways of phosphorylation that work synergistically, providing a rapid interpretation of the most critical pathways in each dataset. MAPPINGS confirmed several signalling interactions previously shown to be modulated by infection, and revealed additional interactions which could form the basis of numerous future studies. The MAPPINGS analysis strategy described here is widely applicable to comparative phosphorylation datasets in any context (e.g. response of cells to infection, treatment, or comparison between differentiation stages of any cell populations) and provides a rapid and reliable analysis to guide validation studies.

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Identification of tyrosine kinase inhibitors that halt Plasmodium falciparum parasitemia

Cited by 15 publications

References 59 publications

Cell physiology and molecular mechanism of anion transport by erythrocyte band 3/AE1

Cell physiology and molecular mechanism of anion transport by erythrocyte band 3/AE1

Network analysis of large phospho-signalling datasets: application to Plasmodium-erythrocyte interactions

MAPPINGS v1.0, a tool for network analysis of large phospho-signalling datasets: application to host erythrocyte response to Plasmodium infection

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