DNA polymerases of herpesviruses and their inhibitors

Human herpesviruses are large double-stranded DNA viruses belonging to the Herpesviridae family. The main characteristics of these viruses are their ability to establish a lifelong latency into the host with a potential to reactivate periodically. Primary infections and reactivations with herpesviruses are responsible for a large spectrum of diseases and may result in severe complications in immunocompromised patients. The viral DNA polymerase is a key enzyme in the replicative cycle of herpesviruses, and the target of most antiviral agents (i.e., nucleoside, nucleotide and pyrophosphate analogs). However, long-term prophylaxis and treatment with these antivirals may lead to the emergence of drug-resistant isolates harboring mutations in genes encoding viral enzymes that phosphorylate drugs (nucleoside analogs) and/or DNA polymerases, with potential cross-resistance between the different analogs. Drug resistance mutations mainly arise in conserved regions of the polymerase and exonuclease functional domains of these enzymes. In the polymerase domain, mutations associated with resistance to nucleoside/nucleotide analogs may directly or indirectly affect drug binding or incorporation into the primer strand, or increase the rate of extension of DNA to overcome chain termination. In the exonuclease domain, mutations conferring resistance to nucleoside/nucleotide analogs may reduce the rate of excision of incorporated drug, or continue DNA elongation after drug incorporation without excision. Mutations associated with resistance to pyrophosphate analogs may alter drug binding or the conformational changes of the polymerase domain required for an efficient activity of the enzyme. Novel herpesvirus inhibitors with a potent antiviral activity against drug-resistant isolates are thus needed urgently.