作者: de Oliveira, Ketllyn Irene Zagato ; Gomes Jardim, Ana Carolina ; Noske, Gabriela Dias ; Oliva, Glaucius ; Fernandes, Rafaela Sachetto ; Gawriljuk, Victor Oliveira ; Santos, Igor Andrade ; de Godoy, Andre Schutzer

The 2015/16 Zika virus (ZIKV) epidemic led to almost 1 million confirmed cases in 84 countries and was associated to the development of congenital microcephaly and Guillain-Barré syndrome. More recently, a ZIKV African lineage was identified in Brazil raising concerns about a future outbreak. The long-term consequences of viral infection emphasizes the need for the development of effective anti-ZIKV drugs. In this study, we developed and characterized a ZIKV replicon cell line for the screening of viral replication inhibitors. The replicon system was developed by engineering the IRES-Neo cassette into the 3' UTR terminus of the ZIKV Rluc DNA construct. After in vitro transcription, replicon RNA was used to transfect BHK-21 cells, that were selected with G418, thus generating the BHK-21-RepZIKV_IRES-Neo cell line. Through this replicon-based cell system, we identified two molecules with potent anti-ZIKV activities, an imidazonaphthyridine and a riminophenazine, both from the MMV/DNDi Pandemic Response Box library of 400 drug-like compounds. The imidazonaphthyridine, known as RO8191, showed remarkable selectivity against ZIKV, while the riminophenazine, the antibiotic Clofazimine, could act as a non-nucleoside analog inhibitor of viral RNA-dependent RNA polymerase (RdRp), as evidenced both in vitro and in silico. The data showed herein supports the use of replicon-based assays in high-throughput screening format as a biosafe and reliable tool for antiviral drug discovery.

2020-06-01·Acta Tropica3区 · 医学

Screening and Identification of Pathogen Box® Compounds with anti-Trypanosoma evansi Activity

3区 · 医学

Article

作者: Miletti, Luiz Claudio ; Canever, Mariana Feltrin

The development of new drugs targeting neglected animal diseases is imperative. In Asia and South America, Trypanosoma evansi is a pathogen that affects horses and other species, causing economic losses associated with reduced animal productivity and death. In order to accelerate the identification of drugs with activity against neglected diseases, Medicines for Malaria Venture has developed Pathogen Box®, a library of 400 different molecules. The present work aimed to identify compounds present in the Pathogen Box® library, measuring in vitro activity against T. evansi. Among the 400 compounds, 5 showed anti-T.evansi activity: pentamidine, MMV688410, MMV687273, MMV022478 and auranofin. Suramin, a trypanocidal activity molecule present on the Pathogen Box® reference compound list, demonstrated no anti-T. evansi activity in the in vitro assays. MMV688410 is the most promising candidate because it induces death and reduces the number of parasites in cell culture, and mainly because its mechanism of action is probably associated with inhibition of trypanosomal reductase enzyme, an exclusive target of trypanosomatides. Further in vitro and in vivo assays are needed to determine the efficacy of the compounds identified in this work, especially by associating tissue distribution and the ability of drugs to cross the blood brain barrier, as T. evansi is able to invade the central nervous system.

2019-01-11·ACS Infectious Diseases2区 · 医学

Early Antischistosomal Leads Identified from in Vitro and in Vivo Screening of the Medicines for Malaria Venture Pathogen Box

2区 · 医学

Article

作者: Laleu, Benoît ; Pasche, Valérian ; Keiser, Jennifer

As part of the control and elimination strategy of human schistosomiasis, preventive chemotherapy relies on a single drug, praziquantel. Facing an almost dry drug development pipeline, screening the Pathogen Box from the Medicines for Malaria Venture (MMV), provides a unique opportunity to possibly expand the pool of potent molecules against schistosomiasis. The activity of 400 compounds from this open-access library was first screened in vitro on the larval stage of Schistosoma mansoni. The hits were then tested on adult worms. Eleven leads were identified and tested for albumin-binding and activity on adult S. haematobium. In parallel, a rudimental structure-activity relationship analysis was performed on the 112 available analogues of three leads, yielding another 30 molecules active against both larval and adult stages of S. mansoni. Seven leads, selected on druglikeness, pharmacokinetic properties, and availability, plus auranofin were tested in mice harboring a chronic S. mansoni infection. MMV022029 and MMV022478 revealed the highest worm burden reductions of 67.8 and 70.7%, respectively. This study provided a series of new potent scaffolds and pharmacophores that could be used to design and develop suitable alternative(s) to praziquantel.

100 项与 MMV687273 相关的药物交易

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