Designing inhibitors or activators for A3s has been extremely challenging. Our results implicate a need to incorporate the structural context of the target deoxycytidine in the therapeutic design. Larger macrocycles may serve as more appropriate starting scaffolds in designing cancer therapies targeting A3s, which would mimic the “U” shape of the bound ssDNA. Macrocycles have recently been shown to have good drug-like properties and may be a strategy to target these critical enzymes38.