Seven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A.

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dc.citation.issue24
dc.citation.volume21
dc.contributor.authorKurup HM
dc.contributor.authorKvach MV
dc.contributor.authorHarjes S
dc.contributor.authorJameson GB
dc.contributor.authorHarjes E
dc.contributor.authorFilichev VV
dc.coverage.spatialEngland
dc.date.accessioned2024-07-18T21:18:59Z
dc.date.available2024-07-18T21:18:59Z
dc.date.issued2023-06-21
dc.description.abstractThe APOBEC3 (APOBEC3A-H) enzyme family as a part of the human innate immune system deaminates cytosine to uracil in single-stranded DNA (ssDNA) and thereby prevents the spread of pathogenic genetic information. However, APOBEC3-induced mutagenesis promotes viral and cancer evolution, thus enabling the progression of diseases and development of drug resistance. Therefore, APOBEC3 inhibition offers a possibility to complement existing antiviral and anticancer therapies and prevent the emergence of drug resistance, thus making such therapies effective for longer periods of time. Here, we synthesised nucleosides containing seven-membered nucleobases based on azepinone and compared their inhibitory potential against human cytidine deaminase (hCDA) and APOBEC3A with previously described 2'-deoxyzebularine (dZ) and 5-fluoro-2'-deoxyzebularine (FdZ). The nanomolar inhibitor of wild-type APOBEC3A was obtained by the incorporation of 1,3,4,7-tetrahydro-2H-1,3-diazepin-2-one in the TTC loop of a DNA hairpin instead of the target 2'-deoxycytidine providing a Ki of 290 ± 40 nM, which is only slightly weaker than the Ki of the FdZ-containing inhibitor (117 ± 15 nM). A less potent but notably different inhibition of human cytidine deaminase (CDA) and engineered C-terminal domain of APOBEC3B was observed for 2'-deoxyribosides of the S and R isomers of hexahydro-5-hydroxy-azepin-2-one: the S-isomer was more active than the R-isomer. The S-isomer shows resemblance in the position of the OH-group observed recently for the hydrated dZ and FdZ in the crystal structures with APOBEC3G and APOBEC3A, respectively. This shows that 7-membered ring analogues of pyrimidine nucleosides can serve as a platform for further development of modified ssDNAs as powerful A3 inhibitors.
dc.description.confidentialfalse
dc.edition.edition2023
dc.format.pagination5117-5128
dc.identifier.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/37282621
dc.identifier.citationKurup HM, Kvach MV, Harjes S, Jameson GB, Harjes E, Filichev VV. (2023). Seven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A.. Org Biomol Chem. 21. 24. (pp. 5117-5128).
dc.identifier.doi10.1039/d3ob00392b
dc.identifier.eissn1477-0539
dc.identifier.elements-typejournal-article
dc.identifier.issn1477-0520
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/70234
dc.languageeng
dc.publisherRoyal Society of Chemistry
dc.publisher.urihttps://pubs.rsc.org/en/content/articlelanding/2023/ob/d3ob00392b
dc.relation.isPartOfOrg Biomol Chem
dc.rights© The Royal Society of Chemistry 2023
dc.rightsCC BY-NC 3.0
dc.rights.urihttps://creativecommons.org/licenses/by-nc/3.0/
dc.subjectHumans
dc.subjectProteins
dc.subjectCytidine Deaminase
dc.subjectMutagenesis
dc.subjectNeoplasms
dc.subjectMinor Histocompatibility Antigens
dc.titleSeven-membered ring nucleobases as inhibitors of human cytidine deaminase and APOBEC3A.
dc.typeJournal article
pubs.elements-id462020
pubs.organisational-groupOther
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