Splice variants in the proteome: a promising and challenging field to targeted drug discovery

Tavares, Raphael; Scherer, Nicole de Miranda; Ferreira, Carlos Gil; Passetti, Fábio

doi:10.1016/j.drudis.2014.11.002

Cited by 14 publications

(9 citation statements)

References 71 publications

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“…Advances in microarray and next generation sequencing (NGS)-based transcriptome profiling (RNA-seq) have already identified novel molecular pathways or key genes associated with the development of disease states in the mouse retina [22-30]. Although transcriptome studies have been applied to low-dose pharmacological treatments in disease models to evaluate drug efficacy and side effects [30-34], RNA-seq studies have rarely been used in the early stages of drug discovery to characterize the cell models used for high throughput screening and to investigate a lead compound's mechanism of action. [30, 35, 36].…”

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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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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“…To further characterize the translational products of identified AS events, we carried out a qualitative proteomic profiling using tandem mass spectrometry (MS/MS) for both control and hypoxia-treated samples (Alfaro et al, 2014; Tavares et al, 2015; Zhu et al, 2017). Proteomic analysis this time generated 547,545 and 485,392 high-quality spectra for control and hypoxia-treated samples, respectively.…”

Section: Resultsmentioning

confidence: 99%

Alternative splicing and translation play important roles in parallel with transcriptional regulation during rice hypoxic germination

Chen

Zhu

Wang³

et al. 2018

Preprint

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9Post-transcriptional mechanisms, including alternative splicing (AS) and alternative 4 0 translation initiation (ATI), have been used to explain the protein diversity involved in 4 1 plant developmental processes and stress responses. Rice germination under hypoxia 4 2conditions is a classical model system for the study of low oxygen stress. It is known 4 3 that there is transcriptional regulation during rice hypoxic germination, but the 4 4 potential roles of AS and ATI in this process are not well understood. In this study, a 4 5proteogenomic approach was used to integrate the data from RNA sequencing, 4 6qualitative and quantitative proteomics to discover new players or pathways in the 4 7response to hypoxia stress. The improved analytical pipeline of proteogenomics led to 4 8the identification of 10,253 intron-containing genes, 1,729 of which were not present 4 9

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“…Therefore, a major focus of current research in this area is in the application of novel technologies for identifying and analyzing target molecules [1,2]. Above all, comprehensive analysis (omics) technology plays an important role in identifying new drug discovery targets [3][4][5]. The in vivo search for molecules using this technology is recognized as one such approach, together with technological innovations such as the use of next-generation sequencing [6,7].…”

Section: Introductionmentioning

confidence: 99%

Search for drug discovery targets focusing on cancer stroma

Kamada

2019

Translational and Regulatory Sciences

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In recent years, it has become clear that the interstitial tissue structure varies markedly between the normal healthy state and various disease states. Focusing on differences in interstitial structure is expected to lead to the discovery of new targets for drugs. Considerable attention is currently focused on approaches that utilize organoids. The organoids retain the structure of the tissue, thereby facilitating identification of drugs that target interstitial tissues including neovascular vessels. Furthermore, protein expression analysis techniques have been developed that focus on the tissue structure based on an approach using chemical proteomics. In this mini-review, we will summarize the latest technological innovations aimed at identifying target molecules that are useful for the development of biopharmaceuticals, including antibody drugs.

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Splice variants in the proteome: a promising and challenging field to targeted drug discovery

Cited by 14 publications

References 71 publications

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

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

Alternative splicing and translation play important roles in parallel with transcriptional regulation during rice hypoxic germination

Search for drug discovery targets focusing on cancer stroma

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