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Integrative computational approach identifies drug targets in CD4⁺ T-cell-mediated immune disorders.

ABSTRACT: CD4⁺ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune-related diseases. CD4⁺ T cells' metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop genome-scale models of naïve, Th1, Th2, and Th17 CD4⁺ T-cell subtypes to map metabolic perturbations in rheumatoid arthritis, multiple sclerosis, and primary biliary cholangitis. We subjected these models to in silico simulations for drug response analysis of existing FDA-approved drugs and compounds. Integration of disease-specific differentially expressed genes with altered reactions in response to metabolic perturbations identified 68 drug targets for the three autoimmune diseases. In vitro experimental validation, together with literature-based evidence, showed that modulation of fifty percent of identified drug targets suppressed CD4⁺ T cells, further increasing their potential impact as therapeutic interventions. Our approach can be generalized in the context of other diseases, and the metabolic models can be further used to dissect CD4⁺ T-cell metabolism.

SUBMITTER: Puniya BL

PROVIDER: S-EPMC7822845 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Integrative computational approach identifies drug targets in CD4+ T-cell-mediated immune disorders.

Puniya Bhanwar Lal BL Amin Rada R Lichter Bailee B Moore Robert R Ciurej Alex A Bennett Sydney J SJ Shah Ab Rauf AR Barberis Matteo M Helikar Tomáš T

NPJ systems biology and applications 20210122 1

CD4+ T cells provide adaptive immunity against pathogens and abnormal cells, and they are also associated with various immune-related diseases. CD4+ T cells' metabolism is dysregulated in these pathologies and represents an opportunity for drug discovery and development. Genome-scale metabolic modeling offers an opportunity to accelerate drug discovery by providing high-quality information about possible target space in the context of a modeled disease. Here, we develop gen ...[more]

PMID: 33483502

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Integrative computational approach identifies drug targets in CD4⁺ T-cell-mediated immune disorders.

Publications

Integrative computational approach identifies drug targets in CD4<sup>+</sup> T-cell-mediated immune disorders.

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