Abstract
To detect drug candidates for dengue haemorrhagic fever (DHF), we employed a computational drug repositioning method to perform an integrated multiple omics analysis based on transcriptomic, proteomic, and interactomic data. We identified 3,892 significant genes, 389 proteins, and 221 human proteins by transcriptomic analysis, proteomic analysis, and human–dengue virus protein–protein interactions, respectively. The drug candidates were selected using gene expression profiles for inverse drug–disease relationships compared with DHF patients and healthy controls as well as interactomic relationships between the signature proteins and chemical compounds. Integrating the results of the multiple omics analysis, we identified eight candidates for drug repositioning to treat DHF that targeted five proteins (ACTG1, CALR, ERC1, HSPA5, SYNE2) involved in human–dengue virus protein–protein interactions, and the signature proteins in the proteomic analysis mapped to significant pathways. Interestingly, five of these drug candidates, valparoic acid, sirolimus, resveratrol, vorinostat, and Y-27632, have been reported previously as effective treatments for flavivirus-induced diseases. The computational approach using multiple omics data for drug repositioning described in this study can be used effectively to identify novel drug candidates.
Highlights
Mosquito-based diseases, such as malaria, dengue, and chikungunya, are life-threatening, so the development of vaccines and medicines for these diseases is of utmost importance for human health
The 3,892 signature genes that we obtained by integrating the results of the three Gene Expression Omnibus (GEO) datasets are listed in Supplementary Table S1 and are presented in a Venn diagram in Fig. 2, which shows that 88 signature genes were common among the three datasets
By searching STITCH 5.0 for drug candidates based on the proteomic data, we found 548 drug candidates that interacted with the 389 significant proteins
Summary
Mosquito-based diseases, such as malaria, dengue, and chikungunya, are life-threatening, so the development of vaccines and medicines for these diseases is of utmost importance for human health. Previous attempts to develop drugs for DHF used structure-based and fragment-based approaches to modify existing potent antiviral agents[4,5,6,7,8] Both in silico and in vitro studies have reported several compounds as being dengue virus inhibitors, only chloroquine[9], celgosivir[10], and balapiravir[11] progressed to clinical trial testing found in databases of clinical studies (ClinicalTrial.gov; https://clinicaltrials.gov/, and Clinical Trial Resister EU: https://www.clinicaltrialsregister.eu/). Chen et al.[17] investigated the repurposing of a library of pharmacologically active compounds (LOPAC1280) using a screening approach with Huh-7 cells and identified three compounds, N-desmethylclozapine, fluoxetine hydrochloride, and salmeterol xinafoate, as dengue virus inhibitors None of these candidate dengue virus inhibitors have advanced to clinical trials in human. The identified drug candidates are expected to induce a suppressed level of gene expression and disrupt the association of host proteins with dengue virus proteins
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