Geoff Jameson with Vyacheslav V Filichev and Elena Harjes, Harikrishnan M Kurup, Maitsetseg Bayarjargal, Jana Filitcheva, Yongdong Su, Tracy K. Hale (Massey University), and international collaborators (University of Minnesota–Twin Cities, Howard Hughes Medical Institute, University of Texas Health San Antonio)
The APOBEC3A enzyme is part of our innate immune response against viruses. However, APOBEC3A can mistakenly target host DNA, causing mutations that stimulate cancer tumour development and drug resistance.
Inhibitors for APOBEC3A are needed to increase the effectiveness of front-line treatments during cancer therapy.
The research team used the Macromolecular Crystallography (MX2) beamline to resolve the molecular structure of APOBEC3A. They found that specific hairpin-shaped DNA was a potent and specific inhibitor of APOBEC3A. These inhibitors are stable, effective in cells, and could be developed into anti-cancer therapies.
The inhibitors discovered by the team are 1,000 times more potent than current alternatives, exhibit low toxicity, and are capable of nuclear uptake. The studies are patent protected, with international patenting underway.
DNA hairpin inhibitors offer a promising solution to limit the activity of APOBEC3A, thereby reducing the likelihood of drug resistance and uncontrolled tumour growth. Once developed, these inhibitors can be used to extend the effectiveness of cancer treatments.
Reference:
Harjes H, Kurup HM, Rieffer AE, Bayarjargal M, Filitcheva J, Su Y, Hale TK, Filichev VV, Harjes E, Harris RS and Jameson GB. 2023. Structure-guided inhibition of the cancer DNA-mutating enzyme APOBEC3A. Nature Communications 14:6382. https://doi.org/10.1038/s41467-023-42174-w
