Moxidectin for COVID-19

<title>Abstract</title> <p>Background Coronavirus disease 2019 (COVID-19) pandemic has led to numerous cases of acute respiratory distress syndrome (ARDS), with a significant number of survivors developing pulmonary fibrosis as a chronic sequela. This condition poses severe long-term health challenges, significantly burdening public health systems. Despite significant research on the acute phase of COVID-19, the mechanisms underlying pulmonary fibrosis following COVID-19 associated ARDS remain poorly understood, and effective therapies are yet to be established. This study aims to elucidate the molecular mechanisms, identify potential biomarkers, and explore therapeutic options for pulmonary fibrosis post-COVID-19-related ARDS through comprehensive transcriptomic and bioinformatic analyses. Methods We collected datasets from Gene Expression Omnibus (GEO) database, including transcriptional profiles of COVID-19, ARDS, and pulmonary fibrosis. Differentially expressed genes (DEGs) common to these conditions were identified, reflecting the transcriptional landscape of pulmonary fibrosis post-COVID-19 ARDS. Functional and pathway enrichment analyses was conducted. Protein-protein interaction (PPI) network was constructed to determine the hub genes and their regulatory networks. Drugs that interact with hub genes were explored and gene-disease associations were analyzed to identify potential therapeutic strategies. Results We identified 116 common DEGs among COVID-19, ARDS, and pulmonary fibrosis datasets. Functional enrichment highlighted critical processes including inflammatory response, apoptosis, transcription regulation, and MAPK cascade. PPI network revealed hub genes which may play crucial roles in the pathogenesis of pulmonary fibrosis post-COVID-19-related ARDS. Notably, FCER1A, associated with immune response and inflammation, GATA2, involved in macrophage function and erythropoiesis, and CLC, indicative of eosinophil activity, emerged as central players. Regulatory network analysis highlighted significant transcription factors (TFs) and microRNAs (miRNAs) associated with hub genes. We found FDA-approved drugs that could interact with these hub genes, including omalizumab, mizolastine, desloratadine, epoetin alfa, and moxidectin. Gene-disease interaction analysis revealed that diseases caused by GATA2 deficiency and immunodeficiency were associated with hub genes. Conclusion Our findings provide valuable insights into the molecular underpinnings of pulmonary fibrosis post-COVID-19 ARDS and highlight potential biomarkers and therapeutic targets. The repurpose of drugs offers a promising avenue for rapid clinical application, potentially improving outcomes. This study provides ideas for improved treatment for pulmonary fibrosis post-COVID-19 ARDS.</p>

Significance COVID-19 is a global pandemic currently lacking an effective cure. We used a cell-based infection assay to screen more than 3,000 agents used in humans and animals and identified 15 with antiinfective activity, ranging from 0.1 nM to 50 μM. We then used in vitro enzymatic assays combined with computer modeling to confirm the activity of those against the viral protease and RNA polymerase. In addition, several herbal medicines were found active in the cell-based infection assay. To further evaluate the efficacy of these promising compounds in animal models, we developed a challenge assay with hamsters and found that mefloquine, nelfinavir, and extracts of Ganoderma lucidum (RF3), Perilla frutescens , and Mentha haplocalyx were effective against SARS-CoV-2 infection.

Some clinical studies have indicated activity of ivermectin, a macrocyclic lactone, against COVID-19, but a biological mechanism initially proposed for this anti-viral effect is not applicable at physiological concentrations. This in silico investigation explores potential modes of action of ivermectin and 14 related compounds, by which the infectivity and morbidity of the SARS-CoV-2 virus may be limited. Binding affinity computations were performed for these agents on several docking sites each for models of (1) the spike glycoprotein of the virus, (2) the CD147 receptor, which has been identified as a secondary attachment point for the virus, and (3) the alpha-7 nicotinic acetylcholine receptor (α7nAChr), an indicated point of viral penetration of neuronal tissue as well as an activation site for the cholinergic anti-inflammatory pathway controlled by the vagus nerve. Binding affinities were calculated for these multiple docking sites and binding modes of each compound. Our results indicate the high affinity of ivermectin, and even higher affinities for some of the other compounds evaluated, for all three of these molecular targets. These results suggest biological mechanisms by which ivermectin may limit the infectivity and morbidity of the SARS-CoV-2 virus and stimulate an α7nAChr-mediated anti-inflammatory pathway that could limit cytokine production by immune cells.