TY - JOUR
T1 - Development of MTH1-binding nucleotide analogs based on 7,8-dihalogenated 7-deaza-dg derivatives
AU - Shi, Hui
AU - Ishikawa, Ren
AU - Heh, Choon Han
AU - Sasaki, Shigeki
AU - Taniguchi, Yosuke
N1 - Funding Information:
This research was funded by Grants-in-Aid for Scientific Research (B), Japan, grant number JP19H03351 for Y.T. and Fukuoka Foundation for Sound Health Cancer Research Fund for Y.T.
Funding Information:
Funding: This research was funded by Grants-in-Aid for Scientific Research (B), Japan, grant number JP19H03351 for Y.T. and Fukuoka Foundation for Sound Health Cancer Research Fund for Y.T.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nu-cleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting mate-rial. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.
AB - MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nu-cleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting mate-rial. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.
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U2 - 10.3390/ijms22031274
DO - 10.3390/ijms22031274
M3 - Article
C2 - 33525366
AN - SCOPUS:85099965655
SN - 1661-6596
VL - 22
SP - 1
EP - 13
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 3
M1 - 1274
ER -