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Substrate-Based Design of Cytosolic Nucleotidase IIIB Inhibitors and Structural Insights into Inhibition Mechanism

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dc.abstract.enCytosolic nucleotidases (cNs) catalyze dephosphorylation of nucleoside 5’-monophosphates and thereby contribute to the regulation of nucleotide levels in cells. cNs have also been shown to dephosphorylate several therapeutically relevant nucleotide analogues. cN-IIIB has shown in vitro a distinctive activity towards 7-mehtylguanosine monophosphate (m7GMP), which is one key metabolites of mRNA cap. Consequently, it has been proposed that cN-IIIB participates in mRNA cap turnover and prevents undesired accumulation and salvage of m7GMP. Here, we sought to develop molecular tools enabling more advanced studies on the cellular role of cN-IIIB. To that end, we performed substrate and inhibitor property profiling using a library of 41 substrate analogs. The most potent hit compounds (identified among m7GMP analogs) were used as a starting point for structure–activity relationship studies. As a result, we identified several 7-benzylguanosine 5’-monophosphate (Bn7GMP) derivatives as potent, unhydrolyzable cN-IIIB inhibitors. The mechanism of inhibition was elucidated using X-ray crystallography and molecular docking. Finally, we showed that compounds that potently inhibit recombinant cN-IIIB have the ability to inhibit m7GMP decay in cell lysates.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorKowalska, Joanna
dc.contributor.authorStrzelecka, Dominika
dc.contributor.authorPanecka-Hofman, Joanna
dc.contributor.authorKubacka, Dorota
dc.contributor.authorJemielity, Jacek
dc.contributor.authorBasquin, Jerome
dc.contributor.authorWojcik, Radoslaw
dc.contributor.authorBaranowski, Marek R.
dc.contributor.authorKozarski, Mateusz
dc.date.accessioned2024-01-26T09:21:08Z
dc.date.available2024-01-26T09:21:08Z
dc.date.issued2022
dc.description.financeŚrodki finansowe przyznane na realizację projektu w zakresie badań naukowych lub prac rozwojowych
dc.description.number5
dc.description.volume15
dc.identifier.doi10.3390/PH15050554
dc.identifier.issn1424-8247
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/121072
dc.identifier.weblinkhttps://www.mdpi.com/1424-8247/15/5/554/pdf
dc.languageeng
dc.pbn.affiliationchemical sciences
dc.relation.ispartofPharmaceuticals
dc.relation.pages554
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleSubstrate-Based Design of Cytosolic Nucleotidase IIIB Inhibitors and Structural Insights into Inhibition Mechanism
dc.typeJournalArticle
dspace.entity.typePublication