Design, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A

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dc.citation.issue22
dc.citation.volume61
dc.contributor.authorKurup HM
dc.contributor.authorKvach MV
dc.contributor.authorHarjes S
dc.contributor.authorBarzak FM
dc.contributor.authorJameson GB
dc.contributor.authorHarjes E
dc.contributor.authorFilichev VV
dc.coverage.spatialUnited States
dc.date.accessioned2023-11-09T02:02:33Z
dc.date.accessioned2023-11-20T01:37:31Z
dc.date.available2022-10-27
dc.date.available2023-11-09T02:02:33Z
dc.date.available2023-11-20T01:37:31Z
dc.date.issued2022-11-15
dc.description.abstractDrug resistance is a major problem associated with anticancer chemo- and immunotherapies. Recent advances in the understanding of resistance mechanisms have revealed that enzymes of the APOBEC3 (A3) family contribute to the development of drug resistance in multiple cancers. A3 enzymes are polynucleotide cytidine deaminases that convert cytosine to uracil (C→U) in single-stranded DNA (ssDNA) and in this way protect humans against viruses and mobile retroelements. On the other hand, cancer cells use A3s, especially A3A and A3B, to mutate human DNA, and thus by increasing rates of evolution, cancer cells escape adaptive immune responses and resist drugs. However, as A3A and A3B are non-essential for primary metabolism, their inhibition opens up a strategy to augment existing anticancer therapies and suppress cancer evolution. To test our hypothesis that pre-shaped ssDNA mimicking the U-shape observed in ssDNA-A3 complexes can provide a better binder to A3 enzymes, a Cu(I)-catalyzed azide-alkyne cycloaddition was used to cross-link two distant modified nucleobases in ssDNA. The resultant cytosine-containing substrate, where the cytosine sits at the apex of the loop, was deaminated faster by the engineered C-terminal domain of A3B than a standard, linear substrate. The cross-linked ssDNA was converted into an A3 inhibitor by replacing the 2'-deoxycytidine in the preferred TCA substrate motif by 2'-deoxyzebularine, a known inhibitor of single nucleoside cytidine deaminases. This strategy yielded the first nanomolar inhibitor of engineered A3BCTD and wild-type A3A (Ki = 690 ± 140 and 360 ± 120 nM, respectively), providing a platform for further development of powerful A3 inhibitors.
dc.description.confidentialfalse
dc.format.pagination2568-2578
dc.identifier.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/36302365
dc.identifier.citationKurup HM, Kvach MV, Harjes S, Barzak FM, Jameson GB, Harjes E, Filichev VV. (2022). Design, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A.. Biochemistry. 61. 22. (pp. 2568-2578).
dc.identifier.doi10.1021/acs.biochem.2c00449
dc.identifier.eissn1520-4995
dc.identifier.elements-typejournal-article
dc.identifier.issn0006-2960
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/69109
dc.languageeng
dc.publisherAmerican Chemical Society
dc.publisher.urihttps://pubs.acs.org/doi/10.1021/acs.biochem.2c00449
dc.relation.isPartOfBiochemistry
dc.rightsCC BY-NC-ND 4.0
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectHumans
dc.subjectOligonucleotides
dc.subjectCytidine Deaminase
dc.subjectDNA, Single-Stranded
dc.subjectCytidine
dc.subjectCytosine
dc.titleDesign, Synthesis, and Evaluation of a Cross-Linked Oligonucleotide as the First Nanomolar Inhibitor of APOBEC3A
dc.typeJournal article
pubs.elements-id457522
pubs.organisational-groupOther
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