NUDT15-mediated hydrolysis limits the efficacy of anti-HCMV drug ganciclovir. Issue 12 (16th December 2021) - Zhang, Si Min
Summary: Ganciclovir (GCV) is the first-line therapy against human cytomegalovirus (HCMV), a widespread infection that is particularly dangerous for immunodeficient individuals. Closely resembling deoxyguanosine triphosphate, the tri-phosphorylated metabolite of GCV (GCV-TP) is preferentially incorporated by the viral DNA polymerase, thereby terminating chain extension and, eventually, viral replication. However, the treatment outcome of GCV varies greatly among individuals, therefore warranting better understanding of its metabolism. Here we show that NUDT15, a Nudix hydrolase known to metabolize thiopurine triphosphates, can similarly hydrolyze GCV-TP through biochemical studies and co-crystallization of the NUDT15/GCV-TP complex. More critically, GCV efficacy was potentiated in HCMV-infected cells following NUDT15 depletion by RNAi or inhibition by an in-house-developed, nanomolar NUDT15 inhibitor, TH8321, suggesting that pharmacological targeting of NUDT15 is a possible avenue to improve existing anti-HCMV regimens. Collectively, the data further implicate NUDT15 as a broad-spectrum metabolic regulator of nucleoside analog therapeutics, such as thiopurines and GCV. Graphical abstract: Highlights: NUDT15 hydrolyzes the active metabolites of antiherpes ganciclovir Depletion of NUDT15 via RNAi potentiates the anti-HCMV efficacy of ganciclovir Nanomolar NUDT15 inhibitor TH8321 demonstrates submicromolar cellular activity Application of TH8321 potentiates the anti-HCMV efficacy of ganciclovir Abstract : Zhang et al. show that the hydrolyase NUDT15 dephosphorylates the active metabolite of antiherpes ganciclovir and thereby limits its efficacy. NUDT15 inhibition via an in-house-developed nanomolar inhibitor TH8321 significantly potentiates ganciclovir, recapitulating NUDT15 depletion. Overall, this suggests that targeting NUDT15 is a potential avenue to improve the current antiherpes therapy.