Dataset Information

Drug repurposing of anti-infective clinical drugs: Discovery of two potential anti-cytokine storm agents.

ABSTRACT: Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-? using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and imipenem efficiently suppressed the release of inflammatory cytokines by partly intervention of NF-?B activity. The acute lung injury was also alleviated and the survival time was prolonged in mice. In addition, entecavir and imipenem inhibited the release of TNF-? and IL-10 in human peripheral blood mononuclear cells (hPBMCs). Collectively, we proposed that entecavir and imipenem might be candidates for the treatment of CSS.

SUBMITTER: Su L

PROVIDER: S-EPMC7443334 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Drug repurposing of anti-infective clinical drugs: Discovery of two potential anti-cytokine storm agents.

Su Li L Tu Ye Y Kong De-Pei DP Chen Da-Gui DG Zhang Chen-Xi CX Zhang Wan-Nian WN Zhuang Chun-Lin CL Wang Zhi-Bin ZB

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20200823

Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus -2 (SARS-CoV-2) has been widely spread in the world with a high mortality. Cytokine storm syndrome (CSS) and acute lung injury caused by SARS-CoV-2 infection severely threaten the patients. With the purpose to find effective and low-toxic drugs to mitigate CSS, entecavir and imipenem were identified to reduce TNF-α using a LPS-induced macrophage model from the anti-infective drug library. Entecavir and im ...[more]

PMID: 32846329

Similar Datasets

Project description:Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover "new targets" for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 ?M, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 ?M), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 ?M). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 ?M), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 ?M in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 ?M in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents.

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

Drug repurposing of anti-infective clinical drugs: Discovery of two potential anti-cytokine storm agents.

Publications

Drug repurposing of anti-infective clinical drugs: Discovery of two potential anti-cytokine storm agents.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets