Dataset Information

Sequence-Derived Markers of Drug Targets and Potentially Druggable Human Proteins.

ABSTRACT: Recent research shows that majority of the druggable human proteome is yet to be annotated and explored. Accurate identification of these unexplored druggable proteins would facilitate development, screening, repurposing, and repositioning of drugs, as well as prediction of new drug-protein interactions. We contrast the current drug targets against the datasets of non-druggable and possibly druggable proteins to formulate markers that could be used to identify druggable proteins. We focus on the markers that can be extracted from protein sequences or names/identifiers to ensure that they can be applied across the entire human proteome. These markers quantify key features covered in the past works (topological features of PPIs, cellular functions, and subcellular locations) and several novel factors (intrinsic disorder, residue-level conservation, alternative splicing isoforms, domains, and sequence-derived solvent accessibility). We find that the possibly druggable proteins have significantly higher abundance of alternative splicing isoforms, relatively large number of domains, higher degree of centrality in the protein-protein interaction networks, and lower numbers of conserved and surface residues, when compared with the non-druggable proteins. We show that the current drug targets and possibly druggable proteins share involvement in the catalytic and signaling functions. However, unlike the drug targets, the possibly druggable proteins participate in the metabolic and biosynthesis processes, are enriched in the intrinsic disorder, interact with proteins and nucleic acids, and are localized across the cell. To sum up, we formulate several markers that can help with finding novel druggable human proteins and provide interesting insights into the cellular functions and subcellular locations of the current drug targets and potentially druggable proteins.

SUBMITTER: Ghadermarzi S

PROVIDER: S-EPMC6872670 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Sequence-Derived Markers of Drug Targets and Potentially Druggable Human Proteins.

Ghadermarzi Sina S Li Xingyi X Li Min M Kurgan Lukasz L

Frontiers in genetics 20191115

Recent research shows that majority of the druggable human proteome is yet to be annotated and explored. Accurate identification of these unexplored druggable proteins would facilitate development, screening, repurposing, and repositioning of drugs, as well as prediction of new drug-protein interactions. We contrast the current drug targets against the datasets of non-druggable and possibly druggable proteins to formulate markers that could be used to identify druggable proteins. We focus on the ...[more]

PMID: 31803227

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Project description:Human cytomegalovirus (HCMV) is a significant cause of disease in immune-compromised adults and immune naïve newborns. No vaccine exists to prevent HCMV infection, and current antiviral therapies have toxic side effects that limit the duration and intensity of their use. There is thus an urgent need for new strategies to treat HCMV infection. Repurposing existing drugs as antivirals is an attractive approach to limit the time and cost of new antiviral drug development. Virus-induced changes in infected cells are often driven by changes in cellular kinase activity, which led us to hypothesize that defining the complement of kinases (the kinome), whose abundance or expression is altered during infection would identify existing kinase inhibitors that could be repurposed as new antivirals. To this end, we applied a kinase capture technique, multiplexed kinase inhibitor bead-mass spectrometry (MIB-MS) kinome, to quantitatively measure perturbations in >240 cellular kinases simultaneously in cells infected with a laboratory-adapted (AD169) or clinical (TB40E) HCMV strain. MIB-MS profiling identified time-dependent increases and decreases in MIB binding of multiple kinases including cell cycle kinases, receptor tyrosine kinases, and mitotic kinases. Based on the kinome data, we tested the antiviral effects of kinase inhibitors and other compounds, several of which are in clinical use or development. Using a novel flow cytometry-based assay and a fluorescent reporter virus we identified three compounds that inhibited HCMV replication with IC50 values of <1 μm, and at doses that were not toxic to uninfected cells. The most potent inhibitor of HCMV replication was OTSSP167 (IC50 <1.2 nm), a MELK inhibitor, blocked HCMV early gene expression and viral DNA accumulation, resulting in a >3 log decrease in virus replication. These results show the utility of MIB-MS kinome profiling for identifying existing kinase inhibitors that can potentially be repurposed as novel antiviral drugs.

Dataset Information

Sequence-Derived Markers of Drug Targets and Potentially Druggable Human Proteins.

Publications

Sequence-Derived Markers of Drug Targets and Potentially Druggable Human Proteins.

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