The Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani

Volpedo, Greta; Saljoughian, Noushin; Hamza, Omar; Halsey, Gregory; Ryan, Nathan; Sedmak, Bren E; Seidler, Gabriella R.; Papenfuss, Tracey L.; Oghumu, Steve; Satoskar, Abhay R.

doi:10.1093/infdis/jiy552

Cited by 27 publications

(23 citation statements)

References 42 publications

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“…BALB/c mice of three groups were treated with SSG at a single dose of 70 mg/kg (cf. [34]) body weight of the animal or PBS via intraperitoneal injection at 14 days after infection. All mice were euthanized and dissected after 14 days of treatment.…”

Section: Animal Infection and Treatment With Ssgmentioning

confidence: 99%

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Zheng

Chen

et al. 2020

Parasites Vectors

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Background Leishmaniasis is a neglected tropical disease affecting millions of people worldwide. Emerging drug resistance of Leishmania species poses threaten to the effective control and elimination programme of this neglected tropical disease. Methods In this work, we conducted drug-resistance testing, whole genome resequencing and proteome profiling for a recently reported clinical isolate with supposed drug resistance (HCZ), and two reference sensitive strains (DD8 and 9044) of Leishmania donovani, to explore molecular mechanisms underlying drug resistance in this parasite. Results With reference to DD8 and 9044 strains, HCZ isolate showed higher-level virulence and clear resistance to antimonials in promastigote culture, infected macrophages and animal experiment. Pairwise genomic comparisons revealed genetic variations (86 copy number variations, 271 frameshift mutations in protein-coding genes and two site mutations in non-coding genes) in HCZ isolate that were absent from the reference sensitive strains. Proteomic analysis indicated different protein expression between HCZ isolate and reference strains, including 69 exclusively detected proteins and 82 consistently down-/upregulated molecules in the HCZ isolate. Integrative analysis showed linkage of 12 genomic variations (gene duplication, insertion and deletion) and their protein expression changes in HCZ isolate, which might be associated with pathogenic and antimony-resistant phenotype. Functional annotation analyses further indicated that molecules involved in nucleotide-binding, fatty acid metabolism, oxidation-reduction and transport might play a role in host-parasite interaction and drug-resistance. Conclusions This comprehensive integrative work provided novel insights into the genetic basis underlying virulence and resistance, suggesting new aspects to be investigated for a better intervention against L. donovani and associated diseases.

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Section: Animal Infection and Treatment With Ssgmentioning

confidence: 99%

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Zheng

Chen

et al. 2020

Parasites Vectors

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“…In vivo assays in young hamsters orally treated with amiodarone at 50 and 100 mg/kg/day did not show statistically significant results. Relative efficacy has been described by Varikuti et al (2019), in which ibrutinib, an inhibitor of Bruton tyrosine kinase used to treat B cell cancer, showed a 50% reduction of the parasitic load on the liver and 75% in the spleen of BALB/c mice orally treated with ibrutinib 6 mg/kg/day and a reduction of 35 and 50%, respectively, with 70 mg/kg/day of sodium stibogluconate.…”

Section: Resultsmentioning

confidence: 86%

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis

Souza

Costa

Silva

et al. 2020

Drug Development Research

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Considered prevalent in many countries on five continents, especially in low‐income regions, leishmaniasis is a neglected tropical disease classified by World Health Organization as one of the diseases for which the development of new treatments is a priority. It is an infectious disease caused by protozoa of the genus Leishmania, whose species may cause different clinical manifestations, such as cutaneous and visceral leishmaniasis (VL). Treatment is exclusively by drug therapy, as it has not been possible to develop vaccines yet. Currently available drugs are not fully effective in all cases; they have parenteral administration and exhibit a number of serious and very common adverse effects. The only oral drug available is expensive and it is not available in many endemic countries. Injectable administration is the main problem of treatments, since it requires patients to go to health centers, hospitalization and professional administration, which are conditions that are not adapted to the reality of the poverty conditions of patients with the disease. In this context, the development of an oral medicine has become a focus as it may solve many of these issues. Based on this scenario, this review aimed to investigate which therapeutic alternatives have been studied for the development of oral drugs directed to the treatment of human VL.

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“…The activity was further confirmed by a flow cytometry assay for which bone-marrow-derived macrophages were infected with Ds-Red L. donovani promastigotes that showed fluorescence-emitting amastigotes inside or after bursting from macrophages. To evaluate the transfectant’s infectivity, an in vitro infection study using flow cytometry was used to differentiate live and dead parasites [ 16 ]. The assay was conducted for 72 h at the IC 50 values of the selected compounds for promastigotes, and the absolute fluorescence of infection and the percentage of infected macrophages were measured.…”

Section: Resultsmentioning

confidence: 99%

Bioflavonoid-Induced Apoptosis and DNA Damage in Amastigotes and Promastigotes of Leishmania donovani: Deciphering the Mode of Action

Mehwish

Khan

et al. 2021

Molecules

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Natural products from plants contain many interesting biomolecules. Among them, quercetin (Q), gallic acid (GA), and rutin (R) all have well-reported antileishmanial activity; however, their exact mechanisms of action are still not known. The current study is a step forward towards unveil the possible modes of action of these compounds against Leishmania donovani (the causative agent of visceral leishmaniasis). The selected compounds were checked for their mechanisms of action against L. donovani using different biological assays including apoptosis and necrosis evaluation, effects on genetic material (DNA), quantitative testing of nitric oxide production, ultrastructural modification via transmission electron microscopy, and real-time PCR analysis. The results confirmed that these compounds are active against L. donovani, with IC50 values of 84.65 µg/mL, 86 µg/mL, and 98 µg/mL for Q, GA, and R, respectively. These compounds increased nitric oxide production and caused apoptosis and DNA damage, which led to changes in the treated cells’ ultrastructural behavior and finally to the death of L. donovani. These compounds also suppressed essential enzymes like trypanothione reductase and trypanothione synthetase, which are critical for leishmanial survival. The selected compounds have high antileishmanial potentials, and thus in-vivo testing and further screening are highly recommended.

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The Potent ITK/BTK Inhibitor Ibrutinib Is Effective for the Treatment of Experimental Visceral Leishmaniasis Caused by Leishmania donovani

Abstract: Our findings show that oral Ibrutinib is highly effective for the treatment of VL caused by L. donovani and mediates its anti-leishmanial activity by promoting host immunity. Therefore, Ibrutinib could be a novel host-targeted drug for the treatment of VL.

Cited by 27 publications

References 42 publications

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Integrative genomic, proteomic and phenotypic studies of Leishmania donovani strains revealed genetic features associated with virulence and antimony-resistance

Recent strategies for the development of oral medicines for the treatment of visceral leishmaniasis

Bioflavonoid-Induced Apoptosis and DNA Damage in Amastigotes and Promastigotes of Leishmania donovani: Deciphering the Mode of Action

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