Dataset Information

Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease.

ABSTRACT: Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in silico investigations of drugs, as performed in this work for Dengue fever disease. We analyzed transcriptomic data in the key tissues of liver, spleen and blood profiles and verified that despite transcriptomic differences due to tissue specialization, the common mechanisms of action, "Adrenergic receptor antagonist", "ATPase inhibitor", "NF-kB pathway inhibitor" and "Serotonin receptor antagonist", were identified as druggable (e.g., oxprenolol, digoxin, auranofin and palonosetron, respectively) to oppose the effects of severe Dengue infection in these tissues. These are good candidates for future functional evaluation and clinical trials.

SUBMITTER: Sierra B

PROVIDER: S-EPMC8402662 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease.

Sierra Beatriz B Magalhães Ana Cristina AC Soares Daniel D Cavadas Bruno B Perez Ana B AB Alvarez Mayling M Aguirre Eglis E Bracho Claudia C Pereira Luisa L Guzman Maria G MG

Viruses 20210804 8

Transcriptomics, proteomics and pathogen-host interactomics data are being explored for the in silico-informed selection of drugs, prior to their functional evaluation. The effectiveness of this kind of strategy has been put to the test in the current COVID-19 pandemic, and it has been paying off, leading to a few drugs being rapidly repurposed as treatment against SARS-CoV-2 infection. Several neglected tropical diseases, for which treatment remains unavailable, would benefit from informed in s ...[more]

PMID: 34452405

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Project description:ObjectiveThe repurposing of nitazoxanide, doxycycline and azithromycin may be effective to improve the symptoms in mild and moderate COVID-19 subjects. This study aimed to detect and explain the efficacy of reusing of these drugs in treating COVID-19.MethodsThe study was divided into two parts: clinical and computational parts. In the clinical part, 80 (30 females) subjects with reverse transcription-polymerase chain reaction-confirmed COVID-19 with mild and moderate symptoms were enrolled in the study. Subjects were treated with azithromycin or doxycycline, and nitazoxanide was added to the treatment if the subject had diarrhoea. Subjects were divided into four groups: Group 1: subjects treated with azithromycin (20 subjects); Group 2: subjects treated with doxycycline (20 subjects); Group 3: subjects treated with a combination of nitazoxanide and doxycycline (20 subjects); and Group 4: subjects treated with a combination of nitazoxanide and azithromycin (20 subjects). In the computational part, we docked the three drugs against all currently available COVID-19-related protein targets (viral and non-viral). Subsequently, top hits were subjected to molecular dynamic simulations (MDSs) (50 ns) and binding free energy calculations to further validate the docking experiments and to investigate the binding modes of the potential inhibitors.ResultsThe symptomatic improvement of mild to moderate subjects was seen on the fifth day after starting treatment in Group 3 and Group 4 and on the seventh day in Group 2. However, for Group 1, the symptomatic improvement of mild to moderate subjects was not seen on the fifth day and required replacement by doxycycline to get the symptomatic improvement. None of the subjects needed intensive care admission and no deaths were reported. In silico, results were in good accordance with the clinical outcomes, where both nitazoxanide and doxycycline achieved the best docking scores against the viral ADP-ribose phosphatase (ADPRP) and the human Adaptor-Associated Kinase 1 (AAK1). MDSs revealed that both drugs were stable in their bindings indicating that they can be considered as lead molecules for targeting ADPRP and AAK1.ConclusionThe clinical and computational studies applied on three FDA-approved antimicrobials together with their recent clinical findings revealed that both nitazoxanide and doxycycline have great therapeutic potential against COVID-19. The future in vitro mechanistic investigation may confirm our primary computational outcomes, and in turn, these classes of compounds provide a promising starting point for further anti-COVID-19 therapeutics.

Dataset Information

Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease.

Publications

Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease.

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