Crowdsourced mapping of unexplored target space of kinase inhibitors

Despite decades of intensive search for compounds that modulate the activity of particular protein targets, a large proportion of the human kinome remains as yet undrugged. Effective approaches are therefore required to map the massive space of unexplored compound-kinase interactions for novel and potent activities. Here, we carry out a crowdsourced benchmarking of predictive algorithms for kinase inhibitor potencies across multiple kinase families tested on unpublished bioactivity data. We find the top-performing predictions are based on various models, including kernel learning, gradient boosting and deep learning, and their ensemble leads to a predictive accuracy exceeding that of single-dose kinase activity assays. We design experiments based on the model predictions and identify unexpected activities even for under-studied kinases, thereby accelerating experimental mapping efforts. The open-source prediction algorithms together with the bioactivities between 95 compounds and 295 kinases provide a resource for benchmarking prediction algorithms and for extending the druggable kinome. The IDG-DREAM Challenge carried out crowdsourced benchmarking of predictive algorithms for kinase inhibitor activities on unpublished data. This study provides a resource to compare emerging algorithms and prioritize new kinase activities to accelerate drug discovery and repurposing efforts

Relating underrepresented genomic DNA patterns and tiRNAs: the rule behind the observation and beyond

Abstract Background One of the central problems of post-genomic biology is the understanding of regulatory network of genes. Traditionally the problem is approached from the protein-DNA interaction perspective. In recent years various types of noncoding RNAs appeared on the scene as new potent players of the game. The exact role of these molecules in gene expression control is mostly unknown at present, while their importance is generally recognized. Results The Human and Mouse genomes have been screened with a statistical model for sequence patterns underrepresented in these genomes, and a subset of motifs, named spanions, has been identified. The common portion of the motif lists of the two species is 75% indicating evolutionary conservation of this feature. These motifs are arranged in clusters at close proximity of distinct genetic landmarks: 5' ends of genes, exon side of the exon/intron junctions and 5' ends of 3' UTRs. The length of the clusters is typically in the 20 to 25 bases range. The findings are in agreement with the known C/G bias of promoter regions while access much more sequential information than the simple composition based model. In the Human genome the recently reported transcription initiation RNAs (tiRNAs) are typically transcribed from these spanion clusters according to the presented results. The spanion clusters account for 70% of the published tiRNAs. Apparently, the model access the common statistical feature of this new and mostly uncharacterized non-coding RNA class and, in this way, supports the experimental observations with theoretical background. Conclusions The presented results seem to support the emerging model of the RNA-driven eukaryotic gene expression control. Beyond that, the model detects spanion clusters at genetic positions where no tiRNA counterpart was considered and reported. The GO-term analysis of genes with high concentration of spanion clusters in their promoter proximal region indicates involvement in gene regulatory processes. The results of the analysis suggest that the gene regulatory potential of the small non-coding RNAs is grossly underestimated at present. Reviewers This article was reviewed by Frank Eisenhaber, Sandor Pongor and Rotem Sorek (nominated by Doron Lancet).</p

Increased Baseline Proinflammatory Cytokine Production in Chronic Hepatitis C Patients with Rapid Virological Response to Peginterferon Plus Ribavirin

Background: Chronic hepatitis C (CHC) patients achieving rapid virological response (RVR) on PEG-IFN/ribavirin (P/R) therapy have high chance of sustained virological response (SVR). To analyze host immunological factors associated with RVR, viral kinetics, phenotype distribution and Th1/Th2 cytokine production by peripheral blood mononuclear cells (PBMC) were studied prior to and during P/R therapy. Methods: TNF-α, IFN-γ, IL-2, IL-6, IL-4 and IL-10 production by PBMC were measured after Toll-like receptor 4 (TLR-4) or phorbol myristate acetate/Ionomycin stimulation in 20 healthy controls and in 50 CHC patients before receiving and during P/R therapy. RVR was achieved by 14, complete early virological response (cEVR) by 19 patients and 17 patients were null-responders (NR). Results: Patients with RVR showed an increased baseline TNF-α and IL-6 production by TLR-4 activated monocytes and increased IFN-γ, decreased IL-4 and IL-10 production by lymphocytes compared to non-RVR patients. SVR was also associated with increased baseline TNF-α production and decreased IL-10 levels compared to patients who did not achieve SVR. Baseline IL-2 production was higher in cEVR compared to NR patients. Antiviral treatment increased TNF-α, IL-6 production by monocytes and IFN-γ secretion by lymphocytes and decreased IL-4 and IL-10 production by lymphocytes in cEVR compared to NR patients. Conclusion: RVR was associated with increased baseline proinflammatory cytokine production by TLR-4 stimulated monocytes and by activated lymphocytes. In null-responders and in patients who did not achieve SVR both TLR-4 sensing function and proinflammatory cytokine production were impaired, suggesting that modulation of TLR activity and controlled induction of inflammatory cytokine production may provide further therapeutic strategy for CHC patients non-responding to P/R treatment.Deposited by bulk impor

Peripheral blood mononuclear cell phenotype characteristics in different study groups before antiviral treatment.

<p>The distribution of peripheral blood lymphocyte subsets was similar between study groups. Absolute monocyte count was significantly increased in rapid virological responders compared to early and non-responder patients. Results are expressed as mean±SE.</p>*<p>p<0,05.</p

The effect of PEG-IFN plus ribavirin treatment on Th1/Th2 cytokine production by PMA/Ionomycin stimulated PBMC.

<p>a. IFN-γ production was significantly increased in complete early virological responders during antiviral treatment compared to pretreatment levels and also to null-responders. b. After 4 and 12 weeks of antiviral treatment, a transient increase in IL-2 production was observed in all study groups. c. PEG-IFN plus RBV resulted in decreased IL-6 production in both rapid and complete early virological responders, had a transient effect in null-responders. d. After 24 weeks of treatment, significantly decreased TNF-α production was found in complete early virological responders. e. f. While PEG-IFN/RBV treatment significantly decreased IL-4 and IL-10 levels in complete early virological responders, null-responders showed significantly increased IL-10 production at week 12 or 24. (*p<0,05; **p<0,01).</p

Th2 cytokine production by PMA/Ionomycin stimulated peripheral blood mononuclear cells.

<p>Prior to therapy, IL-4 and IL-10 production was significantly lower in patients who had subsequent rapid viral decline after 4 weeks of treatment compared to non-SVR group. Baseline Th2 cytokine production did not differ between complete early responders and null-responders (Fig. 4a,b). SVR patients associated with significantly lower baseline IL-10 production compared to non-SVR patients (Fig. 4d).</p

The effect of PEG-IFN plus ribavirin treatment on TNF-α and IL-6 production by TLR-4 stimulated monocytes.

<p>After 12 weeks of PEG-IFN plus RBV treatment, the proinflammatory cytokine production of TLR-4 stimulated monocytes was significantly increased in complete early virological responders compared to null-responder patients. Furthermore, proinflammatory cytokine levels showed no changes and remained low in null-responders throughout antiviral therapy. In contrast to cEVR in RVR patients, proinflammatory cytokine production by monocytes was significantly decreased after 4 weeks of treatment (*p<0,05; **p<0,01 compared to baseline values).</p