Tideglusib Inhibits Pif1 Helicase of Bacteroides sp. via an Irreversible and Cys-380-Dependent Mechanism.

ABSTRACT: Pif1 helicase plays multiple roles in maintaining genome stability, which is an attractive therapeutic target for helicase-related diseases, while small molecules targeting Pif1 are not yet available. In this study, we performed a fluorescence polarization-based high-throughput screening and identified that an FDA-approved drug, Tideglusib (TD), could inhibit the DNA-binding activity (IC₅₀ = 6.2 ± 0.4 μM) and ATPase and helicase activity (IC₅₀ = 2-4 μM) of Bacteroides sp. Pif1 (BaPif1), which was also confirmed with human Pif1. In addition, the TD analogue TDZD-8 displayed similar inhibitory effects on Pif1 activities. Notably, TD irreversibly inhibited BaPif1 and severely induced BaPif1 aggregation. Furthermore, inhibition of BaPif1 by TD was significantly att

SUBMITTER: Zhou X 

PROVIDER: S-EPMC9453980 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature