role of proteomics in drug discovery slideshare

Plasma fibrinogen has been qualified as a drug development tool in Chronic Obstructive Pulmonary Disease (COPD) by the COPD foundation biomarker qualification consortium. In the meantime, to ensure continued support, we are displaying the site without styles EASI-tag enables accurate multiplexed and interference-free MS2-based proteome quantification. 11, 1124.e4 (2020). Register a free Taylor & Francis Online account today to boost your research and gain these benefits: Proteomics in the pharmaceutical and biotechnology industry: a look to the next decade, a Department of Microchemistry, Lipidomics and Next Generation Sequencing, Genentech Inc. DNA Way, South San Francisco, CA, USA, b OMNI Department, Genentech Inc. 1 DNA Way, South San Francisco, CA, USA, c Chemical Biology and Therapeutics Department, Novartis Institutes for Biomedical Research, Cambridge, MA, USA. Biol. Paolini, G. V., Shapland, R. H. B., van Hoorn, W. P., Mason, J. S. & Hopkins, A. L. Global mapping of pharmacological space. A mass spectrometry-based proteome map of drug action in lung cancer cell lines. 15, e8438 (2019). Nat. Marx, V. A dream of single-cell proteomics. Bioorg. Noberini, R., Sigismondo, G. & Bonaldi, T. The contribution of mass spectrometry-based proteomics to understanding epigenetics. employed the MBR algorithm (as previously described) to improve the number of proteins identified [Citation5]. Nat. Finding novel candidates for targeted immunotherapies (e.g. This article provides a global analysis of lysine acetylation. The emerging role of RNA as a therapeutic target for small molecules. The observation that the number of biomarker candidates identified in the literature is perhaps a quarter of human proteins, suggests that the candidate discovery process is often not rigorous enough [Citation133]. Lastly, in addition to predicting peptide fragmentation, deep learning can also be used to predict other peptide characteristics such as retention time [Citation54] or collisional cross section [Citation58]. Rev. A genetic perturbation technique that allows sequence-specific activation of transcription. Am. 16, 101114 (2017). This article highlights the current status of the proteomics field, and how it supports drug discovery and development. Interrogating the druggability of the 2-oxoglutarate-dependent dioxygenase target class by chemical proteomics. Itzhak, D. N., Tyanova, S., Cox, J. Biol. Liu, N. et al. Cell Biol. Precursor ions were fragmented in either data dependent acquisition PASEF (ddaPASEF) or data independent acquisition PASEF (diaPASEF) mode and Brunner et al. A number of different techniques have been implemented to feed the protein through the pore including attachment of a DNA tag [Citation34], utilization of an unfoldase [Citation35], or the use of adhering negative ionic detergents [Citation36]. Structural studies yield important insights into protein function, the "druggability" of protein targets for drug discovery, and drug design. This can guide the real world use of the novel therapeutic, without necessarily requiring new biomarkers. Am. Gehringer, M. & Laufer, S. A. Oncologist 18, 314322 (2013). In this case, the covalent library members do not need additional features to be compatible with the workflow (compared to the PAL equivalent mentioned previously), so that throughput becomes a key limiting factor for screening applications. Nature Reviews Drug Discovery thanks Maarten Altelaar, Donald Kirkpatrick and Giulio Superti-Furga for their contribution to the peer review of this work. Lanning, B. R. et al. Opin. 11, 11131123 (2019). Cell 180, 605632 (2020). Nat. The coming years will define how applicable this approach is within a drug development or clinical setting, but the studies such as the one described here are an example of how this approach could relate to important disease models. The commonly used PI3-kinase probe LY294002 is an inhibitor of BET bromodomains. While DIA methods have typically been optimized to maximize the number of proteins identified, recent publications have focused on improving quantitation. Interestingly, only 36 peptides from these distinct ORFs were observed, suggesting that the protein products are not stable and are degraded quickly. Catalytic in vivo protein knockdown by small-molecule PROTACs. Struct. Nat. The Multiplexed Proteome Dynamics Profiling (mPDP) workflow further allows additional differentiation of direct compound-induced protein degradation from downstream effects and has been used, e.g., to compare the effects of the heterobifunctional JQ1-VHL degrader vs. the bromodomain inhibitor JQ1 alone [Citation120]. Recently, multiple IDA approaches have addressed this limitation by performing a real time database search (RTS) and only performing the slower, more accurate quantitative scans when a peptide is confidently identified [Citation28,Citation29]. Becher, I. et al. Combining LOPIT with differential ultracentrifugation for high-resolution spatial proteomics. 24, 2737 (2015). 10, 760767 (2014). Commun. Building on this finding, studies from Ruiz Cuevas et al. Biotechnol. Quantitative reactivity profiling predicts functional cysteines in proteomes. Cancer Cell 34, 396410.e398 (2018). Figure 2. These molecules exist at low copy numbers per cell and direct detection by mass spectrometer typically requires an amount of tumor tissue not available within the course of treatment. Science 356, eaal3321 (2017). Wright, M. H. & Sieber, S. A. Cited by lists all citing articles based on Crossref citations.Articles with the Crossref icon will open in a new tab. Sci. Chuh, K. N. & Pratt, M. R. Chemical methods for the proteome-wide identification of posttranslationally modified proteins. Borrebaeck, C. A. Chemical proteomics uncovers EPHA2 as a mechanism of acquired resistance to small molecule EGFR kinase inhibition. For some analyses that are routinely performed there is still some guess work involved, or at least incorporation of algorithms that make assumptions about the data that is being used as a database or to interpret downstream analyses. Oncogene mimicry as a mechanism of primary resistance to BRAF inhibitors. Advances in proteomics technologies that will impact therapeutic development in the coming years. & Cravatt, B. F. Target discovery in small-molecule cell-based screens by in situ proteome reactivity profiling. Illing, P. T. et al. Cell. Nat. 9, 21002122 (2014). Biol. Drug Discov. Liu, Y., Patricelli, M. P. & Cravatt, B. F. Activity-based protein profiling: the serine hydrolases. Rev. Nature 534, 570574 (2016). In addition to successful target deconvolution for challenging transmembrane target families of interest such as solute carriers (e.g., SLC39A7/ZIP7 [Citation81], SLC25A20 [Citation82]), the introduced covalent bond also allows application to larger scale mapping of protein interactors and ligandable pockets in live cells for chemical libraries based on the PAL probe design principles mentioned above [Citation83,Citation84]. With the development of more sophisticated therapeutic programs and advanced computational methods, the importance of readily available protein abundance data will continue to increase. Chemoproteomics encompasses a number of workflows that aim to identify and characterize drug-target interactions in cells or cell-derived samples such as cell lysates or enriched subcellular fractions. Drug Discov. Wang, T., Wei, J. J., Sabatini, D. M. & Lander, E. S. Genetic screens in human cells using the CRISPR-Cas9 system. Chem. Chem. Proc. Jones, L. H. Expanding chemogenomic space using chemoproteomics. The functional landscape of the human phosphoproteome. Tissue-based map of the human proteome, Mass spectrometric quantification of histone post-translational modifications by a hybrid chemical labeling method, LRRK2 kinase regulates alpha-synuclein propagation via RAB35 phosphorylation, Assessing protein sequence database suitability using de novo sequencing. Lundberg, E. & Borner, G. H. H. Spatial proteomics: a powerful discovery tool for cell biology. Signal to noise ratio (S:N) correlates directly with sensitivity, which in turn impacts dynamic range, the metric of the signal available for detecting peptides or proteins from a complex mixture. However, despite the availability of these tools, and the advantages of using targeted MS to validate promising biomarker candidates identified using MS based discovery experiments, a recent survey of the literature revealed that a large majority of discovery efforts lack validation, and those that are validated utilize immunoassays and not MS [Citation179]. J. Biol. CAS Flanagan, M. E. et al. Taken together, since translational and post-translational events are primary readouts for the cells biological functionality, we expect that proteomics will remain a key technology in the pharmaceutical and biotechnological arena in the coming decade. Rep. 9, 14159 (2019). Soc. Altun, M. et al. Mann, M., Kumar, C., Zeng, W. F. & Strauss, M. T. Artificial intelligence for proteomics and biomarker discovery. Comparision of DDA and DIA MS proteomics with Olink affinity based proteomics platforms illustrating the signigicant increase in proteome coverage that can be achieved by using these complementary approaches. Jones, L. H. Cell permeable affinity- and activity-based probes. Science 348, 13761381 (2015). Rev. High-density proximity mapping reveals the subcellular organization of mrna-associated granules and bodies. For both applications, the identification of peptide sequences enabled triggering of additional scans to improve stable isotope labeling using amino acids in cell culture (SILAC) quantitation through dedicated selected ion monitoring (SIM) scans, improve isobaric labeling quantitation through additional quantitative scans, or localize post-translational modifications (PTMs) by changing the fragmentation parameters. Nat. In the pharmaceutical industry, proteomics has long been utilized as a drug-discovery tool to help understand changes in protein profiles for disease states or protein expression in relation to genomic studies for target discovery or identification [ 1 ]. Science 339, 13281331 (2013). CAS Chem. Nat. Gillet, L. C. et al. The panel was designed based on cross sectional studies, it is perhaps not surprising that while many replicated as diagnostic candidates only a few emerged as monitoring biomarkers and highlights the importance of aligning the discovery experiments with the ultimate intended use. Smith, K. T., Martin-Brown, S. A., Florens, L., Washburn, M. P. & Workman, J. L. Deacetylase inhibitors dissociate the histone-targeting ING2 subunit from the Sin3 complex. While the technologies underlying these platforms have yet to be revealed, it is clear that the coming years will unveil the possibilities of non-mass spectrometry based unbiased and untargeted single molecule sequencing proteomics approaches. A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Chem. post-translational modifications, metabolite concentrations and proteinprotein interactions can also lead to an assay signal (reviewed in Prabhu [Citation117]). The design or use of drugs that act on multiple targets or disease pathways. Nat. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell Syst. 9, 232240 (2013). Franco-Serrano, L. et al. Genomics and Proteomics in Drug Discovery and Development BY SUCHITTA. Biotechnol. Swinney, D. C. & Anthony, J. Since the interrogated target space for each compound subjected to chemoproteomics is the full cellular proteome, databases of chemoproteomics data and their proactive expansion in screening mode will increasingly enable the identification of chemical starting points for these modalities. Finally, global proteomic profiling has seen renewed interest in the context of compound target identification and mechanism of action studies. However, given mounting evidence that transcript abundance does not always correlate with translational and post translational events [Citation5,Citation6], increasing our abilities to detect increasingly lower levels of protein and peptides is imperative if proteomics is to be of maximum utility to biomedical and clinical research and we are to be able to capture a true snapshot of the translational events governing cellular regulation.