ABSTRACT
Background. Macrophages, including lung alveolar macrophages (AM), and monocytes are the first lines of defense against SARS-CoV-2. Several reports have suggested that SARS-CoV-2 can hijack AM and monocytes for replication and viral spread, which may, in turn, drive the cytokine storm associated with severe COVID-19. Herein, we describe one of many advantageous features that EDP-235, a novel and potent SARS-CoV-2 3C-like protease (3CLpro) inhibitor under development as a once-daily oral antiviral therapy for COVID-19, displays - excellent penetration into macrophages and monocytes. Methods. Intracellular uptake of EDP-235 was tested side-by-side with nirmatrelvir in rat lung AM, human monocytes and human macrophages. To determine the in vivo drug distribution into lung AM, rats were dosed orally with 25 mg/kg of EDP-235 or nirmatrelvir and plasma andAMdrug levels were analyzed by LC/MS/MS. Results. The ratios of intracellular to extracellular concentrations of EDP-235 in rat lung AM, human monocytes and human macrophages were 22.8, 22.7 and 30.5, respectively. In contrast, nirmatrelvir had ratios of 1.2 to 1.5 in these cells. Consistent with the in vitro observations, EDP-235 showed favorable rat AM penetration with an AUC0-24 ratio of 28.4 (AM over plasma), and nirmatrelvir had much less rat AM penetration with an AUC0-24 ratio of 0.5 (AM over plasma). EDP-235 had respective AUC0-24 values of 9.6 and 271.9 h*mug/mL in rat plasma and AM, while the AUC0-24 values of nirmatrelvir in rat plasma and AM were 2.7 and 1.2 h*mug/mL, respectively. Conclusion. EDP-235, a novel and potent SARS-CoV-2 3CL protease inhibitor, demonstrated excellent penetration into monocytes and macrophages, including lung AM. EDP-235 has the potential to eliminate the viral replication of SARS-CoV-2 in these critical immune cells, thus mitigating macrophage-mediated cytokine storm in high-risk COVID-19 patients. Clinical trials with EDP-235 for COVID-19 treatment and prevention are ongoing.
ABSTRACT
Depression is a potential life-threatening disorder that afflicts thousands of humans globally, irrespective of age, gender and status. For its subsequent management and treatment, many people have turned towards traditional herbs and their therapeutic effects which bear little or no side effects when compared to the conventionally opted medication. Among such herbs, Eucommia ulmoides Oliver is a TCM herb that has been reported to used in treating depression and associated disorders. However, its mode of action remains to be elucidated from a pharmacological standpoint. This study was conducted to determine and comprehend the mechanism of action of E. ulmoides in the treatment of depression. The formation of ingredients and targets database was carried out for E. ulmoides, where the ingredients subjective to the herb were screened and investigated for their role in treating depression. The related targets were then investigated by the construction of a protein-protein interaction (PPI) network using STITCH database. The Gene Ontology (GO) term enrichment analysis was also conducted using Cytoscape software and its plugin. The results of the literature survey demonstrated that 45 constituents in E. ulmoides, which yielded the presence of 138 potential targets and 14 relative targets to the herb and depression. The PPI network revealed the association of several protein targets such as SLC6A2, HTR2B, ADRB2, MAOA, HTR1B, MAOB, HTR2A and HSP90AA1 with the treatment of depression by E. ulmoides. Furthermore, 28 GO terms were revealed by the annotation clusters of gene function and their relative abundance value, most of which were found to be very closely associated with depression. The current study findings shed light on the effective potential of E. ulmoides in the treatment of depression, as revealed by the in silico analysis that demonstrated the association of several biological pathways and target proteins. The proposed biological processes that may be involved in its anti-depression mechanism could be the monoamine transport, serotonin receptor signaling pathway, and desensitization of G-protein coupled receptor protein signaling pathway, respectively.