Identification of small molecule inhibitors of human COQ7

Tsuganezawa, Keiko; Sekimata, Katsuhiko; Nakagawa, Yukari; Utata, Rei; Nakamura, Kae; Ogawa, Naoko; Koyama, Hiroo; Shirouzu, Mikako; Fukami, Takehiro; Kita, Kiyoshi; Tanaka, Akiko

doi:10.1016/j.bmc.2019.115182

Cited by 5 publications

(8 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: Analysis Of Quinonesmentioning

confidence: 99%

“…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.…”

Section: An Oxazinoquinoline Hcoq7 Inhibitor Has Antitrypanosomal Act...mentioning

confidence: 99%

“…The coq7 gene of T. cruzi was cloned and proven to have high homology to the human coq7 gene [26]. Therefore, human COQ7 (hCOQ7) inhibitors [27,28] are expected to cross-react with and inhibit trypanosomal COQ7 (tCOQ7).…”

Section: Introductionmentioning

confidence: 99%

“…We have recently demonstrated that pyrazole derivatives inhibit hCOQ7 activity [28]. In the preliminary experiments, we selected the most active pyrazole hCOQ7 inhibitor, 1-(5-Chloropyridin-2-yl)-3-phenyl-1H-pyrazol-5-ol, and examined its trypanocidal activity toward the mammalian stage of the parasite.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi (T. cruzi). It was originally a Latin American endemic health problem, but now is expanding worldwide as a result of increasing migration. The currently available drugs for Chagas disease, benznidazole and nifurtimox, provoke severe adverse effects, and thus the development of new drugs is urgently required. Ubiquinone (UQ) is essential for respiratory chain and redox balance in trypanosomatid protozoans, therefore we aimed to provide evidence that inhibitors of the UQ biosynthesis have trypanocidal activities. In this study, inhibitors of the human COQ7, a key enzyme of the UQ synthesis, were tested for their trypanocidal activities because they were expected to cross-react and inhibit trypanosomal COQ7 due to their genetic homology. We show the trypanocidal activity of a newly found human COQ7 inhibitor, an oxazinoquinoline derivative. The structurally similar compounds were selected from the commercially available compounds by 2D and 3D ligand-based similarity searches. Among 38 compounds selected, 12 compounds with the oxazinoquinoline structure inhibited significantly the growth of epimastigotes of T. cruzi. The most effective 3 compounds also showed the significant antitrypanosomal activity against the mammalian stage of T. cruzi at lower concentrations than benznidazole, a commonly used drug today. We found that epimastigotes treated with the inhibitor contained reduced levels of UQ9. Further, the growth of epimastigotes treated with the inhibitors was partially rescued by UQ10 supplementation to the culture medium. These results suggest that the antitrypanosomal mechanism of the oxazinoquinoline derivatives results from inhibition of the trypanosomal UQ synthesis leading to a shortage of the UQ pool. Our data indicate that the UQ synthesis pathway of T. cruzi is a promising drug target for Chagas disease.

show abstract

Section: Analysis Of Quinonesmentioning

confidence: 99%

Section: An Oxazinoquinoline Hcoq7 Inhibitor Has Antitrypanosomal Act...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

“…Some studies have reported inhibitors of CoQ biosynthesis. For example, 4-nitrobenzoic acid (4-NB) is an efficient inhibitor of CoQ biosynthesis that acts by inhibiting PHB-polyprenyl transferase (COQ2) in mammalian cells [22,23], chlorobenzoic acid is also thought to inhibit the same reaction [24,25], and inhibitors of COQ7 have also been identified [26]. Vanillic acid was reported to bypass the requirement for the reaction involving COQ6 [27], while resveratrol was found to induce genes involved in CoQ biosynthesis without increasing CoQ synthesis in rats [28].…”

Section: Introductionmentioning

confidence: 99%

Benzoic acid inhibits Coenzyme Q biosynthesis in Schizosaccharomyces pombe

et al. 2020

View full text Add to dashboard Cite

Coenzyme Q (CoQ, ubiquinone) is an essential component of the electron transport system in aerobic organisms. Human type CoQ10, which has 10 units of isoprene in its quinone structure, is especially valuable as a food supplement. Therefore, studying the biosynthesis of CoQ10 is important not only for increasing metabolic knowledge, but also for improving biotechnological production. Herein, we show that Schizosaccharomyces pombe utilizes p-aminobenzoate (PABA) in addition to p-hydroxybenzoate (PHB) as a precursor for CoQ10 synthesis. We explored compounds that affect the synthesis of CoQ10 and found benzoic acid (Bz) at >5 μg/mL inhibited CoQ biosynthesis without accumulation of apparent CoQ intermediates. This inhibition was counteracted by incubation with a 10-fold lower amount of PABA or PHB. Overexpression of PHB-polyprenyl transferase encoded by ppt1 (coq2) also overcame the inhibition of CoQ biosynthesis by Bz. Inhibition by Bz was efficient in S. pombe and Schizosaccharomyces japonicus, but less so in Saccharomyces cerevisiae, Aureobasidium pullulans, and Escherichia coli. Bz also inhibited a S. pombe ppt1 (coq2) deletion strain expressing human COQ2, and this strain also utilized PABA as a precursor of CoQ10. Thus, Bz is likely to inhibit prenylation reactions involving PHB or PABA catalyzed by Coq2.

show abstract

Design, synthesis and anticancer evaluation of novel half-sandwich Ru(II) complexes bearing pyrazalone moiety: Apoptosis inducers based on mitochondrial dysfunction and G0/G1 arrest

Huang,

Wei

et al. 2024

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

Identification of small molecule inhibitors of human COQ7

Cited by 5 publications

References 35 publications

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

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

Benzoic acid inhibits Coenzyme Q biosynthesis in Schizosaccharomyces pombe

Design, synthesis and anticancer evaluation of novel half-sandwich Ru(II) complexes bearing pyrazalone moiety: Apoptosis inducers based on mitochondrial dysfunction and G0/G1 arrest

Contact Info

Product

Resources

About