high-throughput-screening-for-broad-spectrum-chemical-inhibitors-rna

High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses

RNA viruses are responsible for major human diseases such as flu, bronchitis, dengue, Hepatitis C or measles. They also represent an emerging threat ...

Institut Pasteur, CNRS UMR3523

We report on Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibitory activities of a series of new 3'- and 5'-modified thymidine analogues including α- and β-derivatives. In addition, several analogues were synthesized in which the 4-oxygen was replaced by a more lipophilic sulfur atom to probe the influence of this modification on TMPKmt inhibitory activity. Several compounds showed an inhibitory potency in the low micromolar range, with the 5'-arylthiourea 4-thio-α-thymidine analogue being the most active one (K(i)=0.17 μM). This compound was capable of inhibiting mycobacteria growth at a concentration of 25 μg/mL.

Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase.

Candida albicans is the most prevalent fungal pathogen of humans, causing a wide range of infections from harmless superficial to severe systemic infections. Improvement of the antifungal arsenal is needed since existing antifungals can be associated with limited efficacy, toxicity and antifungal resistance. Here we aimed to identify compounds that act synergistically with echinocandin antifungals and that could contribute to a faster reduction of the fungal burden.

Synergy of the antibiotic colistin with echinocandin antifungals in Candida species.

Human leishmaniases are parasitic diseases causing severe morbidity and mortality. No vaccine is available and numerous factors limit the use of current therapies. There is thus an urgent need for innovative initiatives to identify new chemotypes displaying selective activity against intracellular Leishmania amastigotes that develop and proliferate inside macrophages, thereby causing the pathology of leishmaniasis.

High content analysis of primary macrophages hosting proliferating Leishmania amastigotes: application to anti-leishmanial drug discovery.

Leishmanioses humaines sont des maladies parasitaires, provoquant la mortalit&eacute; et la morbidit&eacute; grave. Aucun vaccin n&#39;est disponible, et de nombreux facteurs limitent l&#39;utilisation des th&eacute;rapies actuelles. Il y a donc un besoin urgent pour des initiatives innovantes identifier de nouveaux ch&eacute;motypes d&eacute;montrant une activit&eacute; s&eacute;lective contre intracellulaire amastigotes de Leishmania qui se d&eacute;veloppent et se multiplient &agrave; l&#39;int&eacute;rieur de macrophages, provoquant ainsi la pathologie de la leishmaniose.

Analyse de contenu &eacute;lev&eacute; de macrophages primaires h&eacute;bergement prolif&eacute;rant amastigotes de Leishmania : application &agrave; la d&eacute;couverte de m&eacute;dicaments anti-leishmanies.

Leishmaniases umani sono malattie parassitarie che causano mortalit&agrave; e morbilit&agrave; grave. Nessun vaccino &egrave; disponibile e numerosi fattori limitano l&#39;utilizzo di terapie attuali. Cos&igrave; c&#39;&egrave; un urgente bisogno di iniziative innovative identificare nuovi chemiotipi visualizzazione attivit&agrave; selettiva contro intracellulare amastigoti di Leishmania che sviluppano e proliferano all&#39;interno dei macrofagi, causando cos&igrave; la patologia della leishmaniosi.

Analisi del contenuto elevato dei macrofagi primari hosting proliferanti amastigoti di Leishmania: applicazione alla scoperta di nuovi farmaci anti-leishmanial.

Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. DD264 was selected out of 41,353 compounds for both its immuno-stimulatory and antiviral properties. While searching for its mode of action, we identified DD264 as an inhibitor of pyrimidine biosynthesis pathway. This metabolic pathway was recently identified as a prime target of broad-spectrum antiviral molecules, but our data unraveled a yet unsuspected link with innate immunity. Indeed, we showed that DD264 or brequinar, a well-known inhibitor of pyrimidine biosynthesis pathway, both enhanced the expression of antiviral genes in human cells. Furthermore, antiviral activity of DD264 or brequinar was found strictly dependent on cellular gene transcription, nuclear export machinery, and required IRF1 transcription factor. In conclusion, the antiviral property of pyrimidine biosynthesis inhibitors is not a direct consequence of pyrimidine deprivation on the virus machinery, but rather involves the induction of cellular immune response.

Article	Year
Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase. Bioorganic & medicinal chemistry\| PubMed ID: 22061826	2011
Synergy of the antibiotic colistin with echinocandin antifungals in Candida species. The Journal of antimicrobial chemotherapy\| PubMed ID: 23378416	2013
High content analysis of primary macrophages hosting proliferating Leishmania amastigotes: application to anti-leishmanial drug discovery. PLoS neglected tropical diseases\| PubMed ID: 23593521	2013
Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity. PLoS pathogens\| PubMed ID: 24098125	2013

Olivier Helynck

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