Evaluation of Connectivity Map shows limited reproducibility in drug repositioning

Lim, Nathaniel; Pavlidis, Paul

doi:10.1101/845693

Cited by 12 publications

(18 citation statements)

References 26 publications

(33 reference statements)

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“…However, TMPRSS2 was not well-imputed by the Connectivity Map (self-correlation = 0.56 between RNA-seq expression and imputed expression). Consistent with a recent preprint on the lack of reproducibility for L1000-based gene imputation values 28 , we did not observe a significant difference in TMPRSS2 expression following estradiol treatment in MCF7 breast cancer cells or PC3 prostate cancer cells (breast cancer and prostate cancer cells were used in RNA-seq studies from above).…”

Section: Literature-wide Screen For Transcriptional Inhibitors Of Sarsupporting

confidence: 91%

Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic Strategy for SARS-CoV-2

Wang¹,

Dhindsa²,

Povysil³

et al. 2020

Preprint

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There is an urgent need to identify effective therapies for COVID-19 given that a broadly available and effective vaccine is likely at least one year away. Here, we identify compounds that transcriptionally inhibit host proteins required for SARS-CoV-2 entry and should be evaluated for efficacy in SARS-CoV-2 viral infection assays. Recognizing the need for immediately available treatment options, we focused particular attention on FDA-approved drugs that could be immediately repurposed to treat COVID-19 patients. By mining publicly available gene expression data, we identify several compounds that down-regulate TMPRSS2, a protein required for SARS-CoV-2 entry that has emerged as a promising therapeutic target. Among these, we find twenty independent studies that implicate estrogen-related and androgen-related compounds as transcriptional modulators of TMPRSS2 expression, suggesting that these drugs and others acting on the pathway may be promising therapeutic candidates for COVID-19 for further testing. It is also noteworthy that TMPRSS2 has highly variable and skewed expression in humans, spanning two orders of magnitude with a small minority of individuals having extremely high expression. Combined with literature showing that TMPRSS2 loss-of-function in mouse is protective against SARS while anti-estrogen treatment predicted to increase TMPRSS2 expression exacerbates SARS, this observation raises the hypothesis that TMPRSS2 expression may positively correlate with severity in COVID-19.

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Section: Literature-wide Screen For Transcriptional Inhibitors Of Sarsupporting

confidence: 91%

Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic Strategy for SARS-CoV-2

Wang¹,

Dhindsa²,

Povysil³

et al. 2020

Preprint

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“…Second, as the previous studies showed, the consistency between prioritization results from the CMap dataset and other connectivity map libraries such as the LINCS library is low ( Lim and Pavlidis, 2019 ). Therefore, LINCS does not reproduce CMap dataset drug prioritization.…”

Section: Discussionmentioning

confidence: 98%

A connectivity map-based drug repurposing study and integrative analysis of transcriptomic profiling of SARS-CoV-2 infection

Mousavi

rahmanian

Sami

2020

Infection, Genetics and Evolution

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Aims The recent outbreak of COVID-19 has become a global health concern. There are currently no effective treatment strategies and vaccines for the treatment or prevention of this fatal disease. The current study aims to determine promising treatment options for the COVID-19 through a computational drug repurposing approach. Materials and methods In this study, we focus on differentially expressed genes (DEGs), detected in SARS-CoV-2 infected cell lines including “the primary human lung epithelial cell line NHBE” and “the transformed lung alveolar cell line A549”. Next, the identified DEGs are used in the connectivity map (CMap) analysis to identify similarly acting therapeutic candidates. Furthermore, to interpret lists of DEGs, pathway enrichment and protein network analysis are performed. Genes are categorized into easily interpretable pathways based on their biological functions, and overrepresentation of each pathway is tested in comparison to what is expected randomly. Key findings The results suggest the effectiveness of lansoprazole, folic acid, sulfamonomethoxine, tolnaftate, diclofenamide, halcinonide, saquinavir, metronidazole, ebselen, lidocaine and benzocaine, histone deacetylase (HDAC) inhibitors, heat shock protein 90 (HSP90) inhibitors, and many other clinically approved drugs as potent drugs against COVID-19 outbreak. Significance Making new drugs remain a lengthy process, so the drug repurposing approach provides an insight into the therapeutics that might be helpful in this pandemic. In this study, pathway enrichment and protein network analysis are also performed, and the effectiveness of some drugs obtained from the CMap analysis has been investigated according to previous researches.

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“…Despite this increased throughput, screening campaigns still need to be performed in discrete batches. Batch effects (and, more generally, technical factors affecting reproducibility) remain the major analytical hurdle in extracting insight from any drug-profiling dataset, either based on transcriptomics [ 33 , 34 ] or other readouts (WEB: ). Proprietary drug profiling endeavors can be modeled after large public efforts such as LINCS Connectivity Map 2.0, which, in addition to releasing openly accessible datasets, sets best practices and provides analytical tools (WEB: ).…”

Section: Transcriptomics—bulk and Single-cell Sequencingmentioning

confidence: 99%

Advances in Genomics for Drug Development

Spreafico

Soriaga

Grosse

et al. 2020

Genes

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Drug development (target identification, advancing drug leads to candidates for preclinical and clinical studies) can be facilitated by genetic and genomic knowledge. Here, we review the contribution of population genomics to target identification, the value of bulk and single cell gene expression analysis for understanding the biological relevance of a drug target, and genome-wide CRISPR editing for the prioritization of drug targets. In genomics, we discuss the different scope of genome-wide association studies using genotyping arrays, versus exome and whole genome sequencing. In transcriptomics, we discuss the information from drug perturbation and the selection of biomarkers. For CRISPR screens, we discuss target discovery, mechanism of action and the concept of gene to drug mapping. Harnessing genetic support increases the probability of drug developability and approval.

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Evaluation of Connectivity Map shows limited reproducibility in drug repositioning

Cited by 12 publications

References 26 publications

Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic Strategy for SARS-CoV-2

Transcriptional Inhibition of Host Viral Entry Proteins as a Therapeutic Strategy for SARS-CoV-2

A connectivity map-based drug repurposing study and integrative analysis of transcriptomic profiling of SARS-CoV-2 infection

Advances in Genomics for Drug Development

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