Transcriptomics-based drug repositioning pipeline identifies therapeutic candidates for COVID-19

Abstract

The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated sixteen of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.

Profiling Transcription Initiation in Peripheral Leukocytes Reveals Severity-Associated Cis-Regulatory Elements in Critical COVID-19

“…The connectivity score from CMap is calculated based on the observed enrichment scores in the queried gene lists relative to transcriptional signatures in the L1000 reference database. The score incorporates a nominal p-value calculated based on the comparison between the query and reference signatures relative to a null distribution of random queries, using the Kolmogorov-Smirnov enrichment statistic, which is then corrected for multiple testing using the false discovery rate method (29,(57)(58)(59).…”

“…For drug repurposing, the connectivity map scores were computed based on the target genes for each TF-network cluster. We hypothesized that the gene expression pattern resulting from the perturbation by a therapeutic compound should negatively correlate with the COVID-19 transcriptional signature as previously shown (58,59). Therefore, we selected those compounds that had significant negative connectivity map scores (i.e.…”

Applying a computational transcriptomics-based drug repositioning pipeline to identify therapeutic candidates for endometriosis

“…In the past, this method has been successfully applied to identify both known and novel treatments for inflammatory bowel disease 8 , dermatomyositis 9 , and liver cancer 10 . In addition, it has been used to identify novel therapeutics for preterm birth 11 and COVID-19 12 , indicating the potential applications of drug repurposing to reproductive health.…”

Large scale peptide screening against main protease of SARS CoV‐2

“…Since the launch of Covid‐19, several FDA‐approved medications have been clinically trialed, including remdesivir, ribavirin, lopinavir, favipiravir, ritonavir, darunavir, arbidol, chloroquine, tocilizumab, hydroxychloroquine, and interferons 30 . However, the majority of these drugs have only made a limited effort to combat the pandemic 32 . Nonetheless, due to the lack of high efficacious medicines and the intensity of the current health crisis, quick identification approaches for preventive and therapeutic tactics should be investigated from all angles 32 .…”

“…However, the majority of these drugs have only made a limited effort to combat the pandemic 32 . Nonetheless, due to the lack of high efficacious medicines and the intensity of the current health crisis, quick identification approaches for preventive and therapeutic tactics should be investigated from all angles 32 . Previously, our lab has executed several computational investigations on peptide therapeutics against numerous infectious proteins of SARS‐CoV‐2 33–35 …”