In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni

Neves, Bruno J.; Braga, Rodolpho C.; Bezerra, José Clecildo Barreto; Cravo, Pedro Vitor Lemos; Andrade, Carolina Horta

doi:10.1371/journal.pntd.0003435

Cited by 54 publications

(47 citation statements)

References 105 publications

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“…mansoni infection model. Finally, we compare our results with findings reported from the above-mentioned screen by Abdulla et al and a recent target-based chemogenomics screen of a dataset of 2,114 proteins by Neves et al [ 17 ], and discuss overlaps and contradictions.…”

Section: Introductionsupporting

confidence: 59%

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Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

et al. 2015

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BackgroundAs plans to expand mass drug treatment campaigns to fight schistosomiasis form, worries about reliance on praziquantel as the sole available treatment motivate the investigation for novel antischistosomal compounds. Drug repurposing might be an inexpensive and effective source of novel antischistosomal leads.Methodology1600 FDA approved compounds were first assayed against Schistosoma mansoni schistosomula at a concentration of 10 µM. Active compounds identified from this screen were advanced to the adult worm screen at 33.33 µM, followed by hit characterization. Leads with complementary pharmacokinetic and toxicity profiles were then selected for in vivo studies.Principal FindingsThe in vitro screen identified 121 and 36 compounds active against the schistosomula and adult stage, respectively. Further, in vitro characterization and comparison with already available pharmacokinetic and toxicity data identified 11 in vivo candidates. Doramectin (10 mg/kg) and clofazimine (400 mg/kg) were found to be active in vivo with worm burden reductions of 60.1% and 82.7%, respectively.Conclusions/SignificanceThe work presented here expands the knowledge of antischistosomal properties of already approved compounds and underscores variations observed between target-based and phenotypic approaches and among laboratories. The two in vivo-active drugs identified in this study, doramectin and clofazimine are widely available and present as novel drug classes as starting points for further investigation.

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Section: Introductionsupporting

confidence: 59%

“…mansoni [ 22 ] as well as public drug databases to conduct an in silico screen of compounds with known targets that theoretically match targets found in the S . mansoni genome and transcriptome [ 17 ]. When we compared their hits to our NTS hits, a moderate overlap was observed ( S2 Table and Fig 3B ).…”

Section: Discussionmentioning

confidence: 99%

Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

et al. 2015

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“…A third approach would be to explore the complete genome of ZIKV 35 , 36 or the recently published genome for ZIKV circulating in the Americas 37 to apply a target-based chemogenomics approach 38 in order to identify approved drugs that may be active against the ZIKV for testing in vitro .…”

Section: Kickstarting Zikv Drug Discoverymentioning

confidence: 99%

Open drug discovery for the Zika virus

et al. 2016

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The Zika virus (ZIKV) outbreak in the Americas has caused global concern that we may be on the brink of a healthcare crisis. The lack of research on ZIKV in the over 60 years that we have known about it has left us with little in the way of starting points for drug discovery. Our response can build on previous efforts with virus outbreaks and lean heavily on work done on other flaviviruses such as dengue virus. We provide some suggestions of what might be possible and propose an open drug discovery effort that mobilizes global science efforts and provides leadership, which thus far has been lacking. We also provide a listing of potential resources and molecules that could be prioritized for testing as in vitro assays for ZIKV are developed. We propose also that in order to incentivize drug discovery, a neglected disease priority review voucher should be available to those who successfully develop an FDA approved treatment. Learning from the response to the ZIKV, the approaches to drug discovery used and the success and failures will be critical for future infectious disease outbreaks.

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“…Two previous studies have used a similar approach in repositioning of approved drugs against P . falciparum apicoplast [ 51 ] and Schistosoma mansoni [ 52 ]. In this study, each P .…”

Section: Introductionmentioning

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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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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In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni

Cited by 54 publications

References 105 publications

Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

Activity Profile of an FDA-Approved Compound Library against Schistosoma mansoni

Open drug discovery for the Zika virus

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

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