In vitro activity of immunosuppressive drugs against Plasmodium falciparum

Malaria causes about half a million deaths annually, with Plasmodium falciparum being responsible for 90% of all the cases. Recent reports on artemisinin resistance in Southeast Asia warrant urgent discovery of novel drugs for the treatment of malaria. However, most bioactive compounds fail to progress to treatments due to safety concerns. Drug repositioning offers an alternative strategy where drugs that have already been approved as safe for other diseases could be used to treat malaria. This study screened approved drugs for antimalarial activity using an in silico chemogenomics approach prior to in vitro verification. All the P. falciparum proteins sequences available in NCBI RefSeq were mined and used to perform a similarity search against DrugBank, TTD and STITCH databases to identify similar putative drug targets. Druggability indices of the potential P. falciparum drug targets were obtained from TDR targets database. Functional amino acid residues of the drug targets were determined using ConSurf server which was used to fine tune the similarity search. This study predicted 133 approved drugs that could target 34 P. falciparum proteins. A literature search done at PubMed and Google Scholar showed 105 out of the 133 drugs to have been previously tested against malaria, with most showing activity. For further validation, drug susceptibility assays using SYBR Green I method were done on a representative group of 10 predicted drugs, eight of which did show activity against P. falciparum 3D7 clone. Seven had IC50 values ranging from 1 μM to 50 μM. This study also suggests drug-target association and hence possible mechanisms of action of drugs that did show antiplasmodial activity. The study results validate the use of proteome-wide target similarity approach in identifying approved drugs with activity against P. falciparum and could be adapted for other pathogens.

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“…falciparum IMPDH and it has been shown to be active against P . falciparum with an IC 50 of 5.4 μM [ 82 ].…”

Section: Discussionmentioning

confidence: 99%

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets

Mogire¹,

Akala

Macharia

et al. 2017

PLoS ONE

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“…However, the time course of reduced mTORC1 activity is strongly suggestive of indirect effects mechanistically distinct from rapamycin. In addition, rapamycin has also been reported to have microbicidal activities against Plasmodium parasites [ 38 ]. However, the in vitro rapamycin concentrations necessary to affect parasite growth are much higher, suggesting this is not the mechanism underlying protection against ECM in most experimental settings [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration

Mejia

Treviño-Villarreal

Reynolds

et al. 2017

Malar J

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BackgroundMaladaptive immune responses during cerebral malaria (CM) result in high mortality despite opportune anti-malarial chemotherapy. Rapamycin, an FDA-approved immunomodulator, protects against experimental cerebral malaria (ECM) in mice through effects on the host. However, the potential for reduced adaptive immunity with chronic use, combined with an incomplete understanding of mechanisms underlying protection, limit translational potential as an adjunctive therapy in CM.ResultsThe results presented herein demonstrate that a single dose of rapamycin, provided as late as day 4 or 5 post-infection, protected mice from ECM neuropathology and death through modulation of distinct host responses to infection. Rapamycin prevented parasite cytoadherence in peripheral organs, including white adipose tissue, via reduction of CD36 expression. Rapamycin also altered the splenic immune response by reducing the number of activated T cells with migratory phenotype, while increasing local cytotoxic T cell activation. Finally, rapamycin reduced brain endothelial ICAM-1 expression concomitant with reduced brain pathology. Together, these changes potentially contributed to increased parasite elimination while reducing CD8 T cell migration to the brain.ConclusionsRapamycin exerts pleotropic effects on host immunity, vascular activation and parasite sequestration that rescue mice from ECM, and thus support the potential clinical use of rapamycin as an adjunctive therapy in CM.

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“…In addition, a certain protective anti-malarial activity can be postulated from in vitro results obtained with immunosuppressive drugs, such as sirolimus and CsA. Instead, for the moment no conclusive data are available for everolimus and mycophenolic acid if tested at standard doses for the clinical use [ 3 , 228 ].…”

Section: Discussionmentioning

confidence: 99%

Solid Organ Transplant and Parasitic Diseases: A Review of the Clinical Cases in the Last Two Decades

2018

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The aim of this study was to evaluate the occurrence of parasitic infections in solid organ transplant (SOT) recipients. We conducted a systematic review of literature records on post-transplant parasitic infections, published from 1996 to 2016 and available on PubMed database, focusing only on parasitic infections acquired after SOT. The methods and findings of the present review have been presented based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. From data published in the literature, the real burden of parasitic infections among SOT recipients cannot really be estimated. Nevertheless, publications on the matter are on the increase, probably due to more than one reason: (i) the increasing number of patients transplanted and then treated with immunosuppressive agents; (ii) the “population shift” resulting from immigration and travels to endemic areas, and (iii) the increased attention directed to diagnosis/notification/publication of cases. Considering parasitic infections as emerging and potentially serious in their evolution, additional strategies for the prevention, careful screening and follow-up, with a high level of awareness, identification, and pre-emptive therapy are needed in transplant recipients.

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In vitro activity of immunosuppressive drugs against Plasmodium falciparum

Cited by 12 publications

References 12 publications

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets

Target-similarity search using Plasmodium falciparum proteome identifies approved drugs with anti-malarial activity and their possible targets

A single rapamycin dose protects against late-stage experimental cerebral malaria via modulation of host immunity, endothelial activation and parasite sequestration

Solid Organ Transplant and Parasitic Diseases: A Review of the Clinical Cases in the Last Two Decades

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