Why is the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine in its diphosphorylated form (PMEApp4-) initially a better substrate for polymerases than (2′-deoxy)adenosine 5′-triphosphate (dATP4-/ATP4-)? Considerations on the mechanism of nucleic acid polymerases

The observation that the antivirally active PMEA in its diphosphorylated form (PMEApp4-) is initially a better substrate for polymerases than dATP4- (ATP4-) can be rationalized by (i) the increased basicity of the phosphonyl group (compared to a phosphoryl group) and (ii) the participation of the ether O atom of PMEApp4- in metal ion binding; both effects together favor M2+ binding at the α group and thus its nucleophilic attack.