Identification of small molecule inhibitors of human COQ7

The ubiquinone synthesis pathway is a promising drug target for Chagas disease

“…These observations indicated that compound 1 inhibited hCOQ7 in HeLa cells resulting in the reduction of UQ 10 and accumulation of DMQ 10 . It is worth to note that compound 1 inhibited hCOQ7 activity at a much lower concentration compared with the effective concentrations (10-20 μM) of the previously reported pyrazole derivatives [28]. Therefore, we examined compound 1 for its trypanocidal activity.…”

“…Inhibitory activity of a compound on hCOQ7 enzyme activity was determined using HeLa cells, because UQ synthesis activity of human cells varies from strain to strain and HeLa cells have high activity and fit for the cell-based evaluation of hCOQ7 activity [28]. HeLa cells (2 × 10 5 cells/well in a 6-well plate or 4 × 10 5 cells/well in a 60 mm culture dish) were inoculated and cultured overnight, and then the test compounds (1-5 μM) were added and co-cultured for a further 2 days.…”

“…In our previous study, hCOQ7 inhibitors have been selected as the compounds that inhibit hCOQ7 hydroxyl activity and thereby lead to accumulation of its substrate molecule, DMQ 10 in HeLa cells [28]. In the study, 36 test compounds were excluded from analysis of quinones because of their inhibitory effects on the growth and adhesion of HeLa cells.…”

“…Thus, a structurally similar compound, (6-chloro-3-(1-phenylethyl)-3,4-dihydro-2H- [1,3]oxazino [5,6-h] The oxazinoquinoline derivative, compound 1, was tested for its inhibitory effect on the hCOQ7 activity by detection of accumulation of DMQ 10 in HeLa cells. In addition to the endogenous UQ synthesis activity, human cells can take up exogenous UQ [39], and the UQ synthesis activity varies widely depending on the cell line [28]. HeLa cells have the higher UQ synthesis activity and are appropriate to use for the cell-based assay for hCOQ7 activity [28].…”

“…In addition to the endogenous UQ synthesis activity, human cells can take up exogenous UQ [39], and the UQ synthesis activity varies widely depending on the cell line [28]. HeLa cells have the higher UQ synthesis activity and are appropriate to use for the cell-based assay for hCOQ7 activity [28]. Quinone fractions were prepared from HeLa cells treated for 2 days with compound 1, and their quinone amounts were analyzed by HPLC (Fig 1).…”