| Autor: |
Kurup HM; School of Natural Sciences, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand. e.harjes@massey.ac.nz.; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1142, New Zealand., Kvach MV; School of Natural Sciences, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand. e.harjes@massey.ac.nz., Harjes S; School of Natural Sciences, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand. e.harjes@massey.ac.nz., Jameson GB; School of Natural Sciences, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand. e.harjes@massey.ac.nz.; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1142, New Zealand., Harjes E; School of Natural Sciences, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand. e.harjes@massey.ac.nz.; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1142, New Zealand., Filichev VV; School of Natural Sciences, Massey University, Private Bag 11 222, Palmerston North 4442, New Zealand. e.harjes@massey.ac.nz.; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1142, New Zealand. |
| Abstrakt: |
The 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-2 H -1,3-diazepin-2-one in the TTC loop of a DNA hairpin instead of the target 2'-deoxycytidine providing a K i of 290 ± 40 nM, which is only slightly weaker than the K i 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. |
