Systems Pharmacology: An opinion on how to turn the impossible into grand challenges

Westerhoff, Hans V.; Nakayama, S.; Mondeel, Thierry D.G.A.; Barberis, Matteo

doi:10.1016/j.ddtec.2015.06.006

Cited by 16 publications

(11 citation statements)

References 21 publications

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“…we found the circuit in sRNA-GA signaling and additionally a link between GA signaling and R-gene expression. The complexity of regulatory responses observed in this study (Fig 5) is in line with the systems biology paradigm that interaction of multiple components and not a single component within a cell leads to much of biological function [48]. Although the reductionist approach is powerful in building logically simple hypotheses and devising ways to test them, it is very difficult to reconstitute the function for a whole biological system based solely on that as the behavior of the system may depend heavily on complex interactions within the system [49].…”

Section: Discussionsupporting

confidence: 85%

Salicylic acid perturbs sRNA-gibberellin regulatory network in immune response of potato toPotato virus Yinfection

Križnik

Petek

Dobnik

et al. 2017

Preprint

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Potato virus Y is the most economically important potato viral pathogen. We aimed at unraveling the roles of small RNAs (sRNAs) in the complex immune signaling network controlling the establishment of tolerant response of potato cv. Désirée to the virus. We constructed a sRNA regulatory network connecting sRNAs and their targets to link sRNA level responses to physiological processes. We discovered an interesting novel sRNAs-gibberellin regulatory circuit being activated as early as 3 days post inoculation before viral multiplication can be detected. Increased levels of miR167 and phasiRNA931 were reflected in decreased levels of transcripts involved in gibberellin biosynthesis. Moreover, decreased concentration of gibberellin confirmed this regulation. The functional relation between lower activity of gibberellin signaling and reduced disease severity was previously confirmed in Arabidopsis-virus interaction using knockout mutants. We further showed that this regulation is salicylic acid-dependent as the response of sRNA network was attenuated in salicylic acid-depleted transgenic counterpart NahG-Désirée expressing severe disease symptoms. Besides downregulation of gibberellin signaling, regulation of several other parts of sRNA network in tolerant Désirée revealed similarities to responses observed in mutualistic symbiotic interactions. The intertwining of different regulatory networks revealed shows how developmental signaling, disease symptom development and stress signaling can be balanced.

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Section: Discussionsupporting

confidence: 85%

Salicylic acid perturbs sRNA-gibberellin regulatory network in immune response of potato toPotato virus Yinfection

Križnik

Petek

Dobnik

et al. 2017

Preprint

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“…This risk can be acceptable for treating terminal diseases or chronic life-threatening infections but not for slowly progressive diseases that are not fatal or overly burdensome during a patient's normal lifespan. To minimize such drug side effects, recent approaches in systems biology can be used to characterize the molecular features of disease models used in both the early and later stages of drug development [1, 2]. Moreover, these technologies can be adapted to improve our understanding of the pharmacology of a starting molecule with respect to its possible off-target effects and therapeutic potential.…”

Section: Introductionmentioning

confidence: 99%

Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa

Chen

Brooks

Gieser

et al. 2017

Pharmacological Research

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Mammalian cells are commonly employed in screening assays to identify active compounds that could potentially affect the progression of different human diseases including retinitis pigmentosa (RP), a class of inherited diseases causing retinal degeneration with compromised vision. Using transcriptome analysis, we compared NIH3T3 cells expressing wildtype (WT) rod opsin with a retinal disease-causing single P23H mutation. Surprisingly, heterologous expression of WT opsin in NIH3T3 cells caused more than a 2-fold change in 783 out of 16,888 protein coding transcripts. The perturbed genes encoded extracellular matrix proteins, growth factors, cytoskeleton proteins, glycoproteins and metalloproteases involved in cell adhesion, morphology and migration. A different set of 347 transcripts was either up- or down-regulated when the P23H mutant opsin was expressed suggesting an altered molecular perturbation compared to WT opsin. Transcriptome perturbations elicited by drug candidates aimed at mitigating the effects of the mutant protein revealed that different drugs targeted distinct molecular pathways that resulted in a similar phenotype selected by a cell-based high-throughput screen. Thus, transcriptome profiling can provide essential information about the therapeutic potential of a candidate drug to restore normal gene expression in pathological conditions.

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“…This shifts the agenda to one of molecular enzymology and systems biology, in which we need to discover (i) which transporters transport which drugs (Giacomini et al, 2010; Sugiyama and Steffansen, 2013), (ii) their expression profiles in different membranes and tissues, and (iii) their kinetic properties. In other words it leads us to recognize that this is fundamentally a problem of systems pharmacology (e.g., van der Greef and Mcburney, 2005; Berger and Iyengar, 2009; van der Graaf and Benson, 2011; Antman et al, 2012; Rostami-Hodjegan, 2012; Waldman and Terzic, 2012; Zhao and Iyengar, 2012; Kell and Goodacre, 2014; Westerhoff et al, 2015; Kell, 2015a). …”

Section: Introductionmentioning

confidence: 99%

Enhancing Drug Efficacy and Therapeutic Index through Cheminformatics-Based Selection of Small Molecule Binary Weapons That Improve Transporter-Mediated Targeting: A Cytotoxicity System Based on Gemcitabine

et al. 2017

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The transport of drug molecules is mainly determined by the distribution of influx and efflux transporters for which they are substrates. To enable tissue targeting, we sought to develop the idea that we might affect the transporter-mediated disposition of small-molecule drugs via the addition of a second small molecule that of itself had no inhibitory pharmacological effect but that influenced the expression of transporters for the primary drug. We refer to this as a “binary weapon” strategy. The experimental system tested the ability of a molecule that on its own had no cytotoxic effect to increase the toxicity of the nucleoside analog gemcitabine to Panc1 pancreatic cancer cells. An initial phenotypic screen of a 500-member polar drug (fragment) library yielded three “hits.” The structures of 20 of the other 2,000 members of this library suite had a Tanimoto similarity greater than 0.7 to those of the initial hits, and each was itself a hit (the cheminformatics thus providing for a massive enrichment). We chose the top six representatives for further study. They fell into three clusters whose members bore reasonable structural similarities to each other (two were in fact isomers), lending strength to the self-consistency of both our conceptual and experimental strategies. Existing literature had suggested that indole-3-carbinol might play a similar role to that of our fragments, but in our hands it was without effect; nor was it structurally similar to any of our hits. As there was no evidence that the fragments could affect toxicity directly, we looked for effects on transporter transcript levels. In our hands, only the ENT1-3 uptake and ABCC2,3,4,5, and 10 efflux transporters displayed measurable transcripts in Panc1 cultures, along with a ribonucleoside reductase RRM1 known to affect gemcitabine toxicity. Very strikingly, the addition of gemcitabine alone increased the expression of the transcript for ABCC2 (MRP2) by more than 12-fold, and that of RRM1 by more than fourfold, and each of the fragment “hits” served to reverse this. However, an inhibitor of ABCC2 was without significant effect, implying that RRM1 was possibly the more significant player. These effects were somewhat selective for Panc cells. It seems, therefore, that while the effects we measured were here mediated more by efflux than influx transporters, and potentially by other means, the binary weapon idea is hereby fully confirmed: it is indeed possible to find molecules that manipulate the expression of transporters that are involved in the bioactivity of a pharmaceutical drug. This opens up an entirely new area, that of chemical genomics-based drug targeting.

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Systems Pharmacology: An opinion on how to turn the impossible into grand challenges

Cited by 16 publications

References 21 publications

Salicylic acid perturbs sRNA-gibberellin regulatory network in immune response of potato toPotato virus Yinfection

Salicylic acid perturbs sRNA-gibberellin regulatory network in immune response of potato toPotato virus Yinfection

Transcriptome profiling of NIH3T3 cell lines expressing opsin and the P23H opsin mutant identifies candidate drugs for the treatment of retinitis pigmentosa

Enhancing Drug Efficacy and Therapeutic Index through Cheminformatics-Based Selection of Small Molecule Binary Weapons That Improve Transporter-Mediated Targeting: A Cytotoxicity System Based on Gemcitabine

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