Pharmacological inhibition of p110δ subunit of PI3K confers protection against experimental leishmaniasis

Khadem, Forough; Jia, Ping; Mou, Zhirong; Barazandeh, Aida Feiz; Liu, Dong; Keynan, Yoav; Uzonna, Jude E.

doi:10.1093/jac/dkw448

Cited by 25 publications

(50 citation statements)

References 47 publications

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“…This could further promote MAPK and NF-κB activity ( Vishwakarma et al, 2018 ). A recent study by Khadem et al (2017) , showed that administration of PI3K p110δ inhibitors CAL-101 and IC87114 resulted in a decrease in parasitic burden in both a CL and VL murine model. This result was accompanied by increased cytokine production in the spleen, livers and footpads of infected mice.…”

Section: Host-targeted Therapeutics and Approaches For Treatment Of Lmentioning

confidence: 99%

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Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

et al. 2018

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The neglected tropical diseases (NTDs) caused by protozoan parasites are responsible for significant morbidity and mortality worldwide. Current treatments using anti-parasitic drugs are toxic and prolonged with poor patient compliance. In addition, emergence of drug-resistant parasites is increasing worldwide. Hence, there is a need for safer and better therapeutics for these infections. Host-directed therapy using drugs that target host pathways required for pathogen survival or its clearance is a promising approach for treating infections. This review will give a summary of the current status and advances of host-targeted therapies for treating NTDs caused by protozoa.

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Section: Host-targeted Therapeutics and Approaches For Treatment Of Lmentioning

confidence: 99%

“…This result was accompanied by increased cytokine production in the spleen, livers and footpads of infected mice. The authors suggest the use of these inhibitors along with amphotericin B for even better outcomes ( Khadem et al, 2017 ).…”

Section: Host-targeted Therapeutics and Approaches For Treatment Of Lmentioning

confidence: 99%

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

et al. 2018

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“…Therapeutic administrations (after one or two weeks) of idelalisib (0.05 mg per mouse) have been shown to significantly ( p <0.05) lower parasite burden in the spleens and livers of L. donovani ‐infected mice. In addition, treatment of infected mice with idelalisib (0.05 mg per mouse) and amphotericin B (0.1 mg kg −1 ) also leads to a complete clearance of parasites both in spleen and in the liver . The decrease in parasite burden was associated with a concomitant reduction in regulatory T cell numbers and cytokine production by the liver, spleen and lymph node cells, as the direct growth of L. donovani promastigotes in axenic was not affected by any concentration tested of idelalisib or IC87114.…”

Section: Human Kinase Inhibitor Repurposing In Trypanosomatidsmentioning

confidence: 91%

“…Two mammalian atypical kinase inhibitors, idelalisib, a p110δ‐specific inhibitor approved for treatment of different B cell malignancies, and IC87114, a mixed PI3K inhibitor, have been evaluated in Leishmania (Figure ) . Prophylactic administrations of idelalisib (0.05 mg per mouse) or IC87114 (0.5 mg per mouse), have been shown to significantly ( p <0.01) decrease lesion size in CL and parasite burdens in VL and CL in the spleen and liver of L. donovani ‐infected mice, and footpad of L. major ‐infected mice.…”

Section: Human Kinase Inhibitor Repurposing In Trypanosomatidsmentioning

confidence: 99%

Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

et al. 2017

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Human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required. The majority of current therapeutic trypanosomatid targets are enzymes or cell‐surface receptors. Among these, eukaryotic protein kinases are a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases. This review summarizes the finding of new hit compounds for neglected tropical protozoan diseases, by repurposing known human kinase inhibitors on trypanosomatids. Kinase inhibitors are grouped by human kinase family and discussed according to the screening (target‐based or phenotypic) reported for these compounds on trypanosomatids. This collection aims to provide insight into repurposed human kinase inhibitors and their importance in the development of new chemical entities with potential beneficial effects on the diseases caused by trypanosomatids.

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“…Another signaling pathway inhibitor, AS-605240 (PI3K gamma inhibitor) has shown to be as efficacious as sodium stibogluconate (SSG) in the treating of L. mexicana infection [92]. Similarly, another PI3K inhibitor CAL-101 and IC87114 are known to effectively reduce parasitic burden by reducing the B-cells and regulatory T-cells populations [93,94]. Another tyrosine kinase inhibitor, ibrutinib has been shown to treat leishmaniasis by triggering T H 1-polarized IFN-γ production [95].…”

Section: Immunomodulatorsmentioning

confidence: 99%

Molecular Medicines for Parasitic Diseases

Singh¹

2021

Methods in Molecular Medicine

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Being the cause for significant amount of morbidities and mortalities, parasitic diseases remain the major challenge for the healthcare community due to the limitations associated with the current chemotherapeutics. Drug discovery/invention can be achieved by collaborative efforts of biotechnologists and pharmacists for identifying potential candidates and successfully turn them into medicine for improving the healthcare system. Although molecular medicine for disease intervention is still in its infancy, however, significant research works and successful trials in short span of time have made it broadly accepted among the scientific community. This chapter identifies different molecular medicine approaches for dealing with parasites that have been coming up on the horizon with the new technological advances in bioinformatics and in the field of omics. With the better understanding of the genomics, molecular medicine field has not only raised hopes to deal with parasitic infections but also accelerated the development of personalized medicine. This will provide a targeted approach for identifying the druggable targets and their pathophysiological importance for disease intervention.

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Pharmacological inhibition of p110δ subunit of PI3K confers protection against experimental leishmaniasis

Cited by 25 publications

References 47 publications

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

Host-Directed Drug Therapies for Neglected Tropical Diseases Caused by Protozoan Parasites

Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases

Molecular Medicines for Parasitic Diseases

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