Dataset Information

LINCS L1000 dataset-based repositioning of CGP-60474 as a highly potent anti-endotoxemic agent.

ABSTRACT: Sepsis is one of the most common clinical syndromes that causes death and disability. Although many studies have developed drugs for sepsis treatment, none have decreased the mortality rate. The aim of this study was to identify a novel treatment option for sepsis using the library of integrated network-based cellular signatures (LINCS) L1000 perturbation dataset based on an in vitro and in vivo sepsis model. Sepsis-related microarray studies of early-stage inflammatory processes in patients and innate immune cells were collected from the Gene Expression Omnibus (GEO) data repository and used for candidate drug selection based on the LINCS L1000 perturbation dataset. The anti-inflammatory effects of the selected candidate drugs were analyzed using activated macrophage cell lines. CGP-60474, an inhibitor of cyclin-dependent kinase, was the most potent drug. It alleviated tumor necrosis factor-? (TNF-?) and interleukin-6 (IL-6) in activated macrophages by downregulating the NF-?B activity, and it reduced the mortality rate in LPS induced endotoxemia mice. This study shows that CGP-60474 could be a potential therapeutic candidate to attenuate the endotoxemic process. Additionally, the virtual screening strategy using the LINCS L1000 perturbation dataset could be a cost and time effective tool in the early stages of drug development.

SUBMITTER: Han HW

PROVIDER: S-EPMC6175892 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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LINCS L1000 dataset-based repositioning of CGP-60474 as a highly potent anti-endotoxemic agent.

Han Hyun-Wook HW Hahn Soojung S Jeong Hye Yun HY Jee Joo-Hyun JH Nam Myoung-Ok MO Kim Han Kyung HK Lee Dong Hyeon DH Lee So-Young SY Choi Dong Kyu DK Yu Ji Hoon JH Min Sang-Hyun SH Yoo Jongman J

Scientific reports 20181008 1

Sepsis is one of the most common clinical syndromes that causes death and disability. Although many studies have developed drugs for sepsis treatment, none have decreased the mortality rate. The aim of this study was to identify a novel treatment option for sepsis using the library of integrated network-based cellular signatures (LINCS) L1000 perturbation dataset based on an in vitro and in vivo sepsis model. Sepsis-related microarray studies of early-stage inflammatory processes in patients and ...[more]

PMID: 30297806

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Project description:The library of integrated network-based cellular signatures (LINCS) L1000 data set currently comprises of over a million gene expression profiles of chemically perturbed human cell lines. Through unique several intrinsic and extrinsic benchmarking schemes, we demonstrate that processing the L1000 data with the characteristic direction (CD) method significantly improves signal to noise compared with the MODZ method currently used to compute L1000 signatures. The CD processed L1000 signatures are served through a state-of-the-art web-based search engine application called L1000CDS2. The L1000CDS2 search engine provides prioritization of thousands of small-molecule signatures, and their pairwise combinations, predicted to either mimic or reverse an input gene expression signature using two methods. The L1000CDS2 search engine also predicts drug targets for all the small molecules profiled by the L1000 assay that we processed. Targets are predicted by computing the cosine similarity between the L1000 small-molecule signatures and a large collection of signatures extracted from the gene expression omnibus (GEO) for single-gene perturbations in mammalian cells. We applied L1000CDS2 to prioritize small molecules that are predicted to reverse expression in 670 disease signatures also extracted from GEO, and prioritized small molecules that can mimic expression of 22 endogenous ligand signatures profiled by the L1000 assay. As a case study, to further demonstrate the utility of L1000CDS2, we collected expression signatures from human cells infected with Ebola virus at 30, 60 and 120 min. Querying these signatures with L1000CDS2 we identified kenpaullone, a GSK3B/CDK2 inhibitor that we show, in subsequent experiments, has a dose-dependent efficacy in inhibiting Ebola infection in vitro without causing cellular toxicity in human cell lines. In summary, the L1000CDS2 tool can be applied in many biological and biomedical settings, while improving the extraction of knowledge from the LINCS L1000 resource.

Dataset Information

LINCS L1000 dataset-based repositioning of CGP-60474 as a highly potent anti-endotoxemic agent.

Publications

LINCS L1000 dataset-based repositioning of CGP-60474 as a highly potent anti-endotoxemic agent.

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