A Transcriptomics-Based Bioinformatics Approach for Identification and In Vitro Screening of FDA-Approved Drugs for Repurposing against Dengue Virus-2

Abstract

The rising incidence of dengue virus (DENV) infections in the tropical and sub-tropical regions of the world emphasizes the need to identify effective therapeutic drugs against the disease. Repurposing of drugs has emerged as a novel concept to combat pathogens. In this study, we employed a transcriptomics-based bioinformatics approach for drug identification against DENV. Gene expression omnibus datasets from patients with different grades of dengue disease severity and healthy controls were used to identify differentially expressed genes in dengue cases, which were then applied to the query tool of Connectivity Map to identify the inverse gene–disease–drug relationship. A total of sixteen identified drugs were investigated for their prophylactic, virucidal, and therapeutic effects against DENV. Focus-forming unit assay and quantitative RT-PCR were used to evaluate the antiviral activity. Results revealed that five compounds, viz., resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat, have significant anti-DENV activity. Further, molecular docking studies showed that these drugs can interact with a variety of protein targets of DENV, including the glycoprotein, the NS5 RdRp, NS2B-NS3 protease, and NS5 methyltransferase The in vitro and in silico results, therefore, reveal that these drugs have the ability to decrease DENV-2 production, suggesting that these drugs or their derivatives could be attempted as therapeutic agents against DENV infections.

Drug repurposing approach against chikungunya virus: an in vitro and in silico study

“…Among the drugs which showed anti CHIKV activity in the present study, resveratrol, doxorubicin, lomibuvir and enalaprilat were also reported to exert anti-DENV activity ( Punekar et al., 2022 ). These drugs might be useful in regions where both viruses are endemic and need to be prioritized.…”

“…Towards the search to discover newer CHIK viral targets and mechanisms for the development of novel antivirals, in the present study, we investigated the anti-CHIKV activity of fourteen FDA-approved drugs. Some of these drugs were identified as potential drug candidates against dengue, another mosquito-borne disease ( Punekar et al., 2022 ) which mimics CHIKF in symptoms ( Table 3 ).…”

“…Resveratrol is an anti-inflammatory drug; earlier, it has been used as a repurposed drug against MERS-CoV infection ( Lin et al., 2017 ). Our recent study reported that resveratrol possesses anti-DENV activity ( Punekar et al., 2022 ). The present study revealed that resveratrol at 12.5 µM and 6.25 µM concentrations significantly inhibited the CHIKV virus.…”

“…The cytotoxic effects and CC50 values of nine drugs have been reported earlier ( Punekar et al., 2022 ) and the drugs at the highest non-toxic concentrations were used for screening of anti-CHIKV activity. For the additional drugs, a cytotoxicity assay was performed using a 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and the percent cell viability and CC50 values were calculated as described earlier ( Punekar et al., 2022 ). A concentration range of 0.78 µM to 200 µM was used for each drug.…”

“…Since both diseases have identical symptoms during the initial phase of the disease, drugs targeting both viruses might provide an advantage in reducing the viral load thereby reducing disease severity. Our recent study identified FDA-approved drugs namely resveratrol, doxorubicin, lomibuvir, elvitegravir, and enalaprilat with anti DENV activity using systems biology approach and in vitro studies ( Punekar et al., 2022 ). Since the drugs had anti-DENV activity, identifying anti-CHIKV activity would add more value to the drugs and might have utility in regions where both the viruses co-circulate and wherein co-infections are more prevalent.…”