Targeting the UL37 deamidase to impede HSV-1 infection.

ABSTRACT Herpesviruses are ubiquitous human pathogens worldwide. Though herpesvirus infections are often asymptomatic in normal individuals, they cause significant morbidity and mortality in immune-compromised individuals. Antivirals have been successfully developed to target the viral thymidine kinase for the past nearly half-century. In the presence of such antivirals, drug- resistance of herpes simplex viruses (HSV), including HSV-1 and HSV-2, is rapidly emerging, particularly in those immune-compromised individuals such as AIDS patients. Thus, new antivirals are desperately needed to cope with the dire situation. We have previously identified the HSV-1 UL37 deamidase that deamidates and inactivates cytosolic RIG-I and cGAS, thereby muting host innate immune defense. The enzymatic activity of UL37 represents an “Achilles heel” that can be targeted to restore host immune defense. Continuing our original discoveries on protein deamidation, we synthesized series of glutamine analogues to identify inhibitors of selected protein deamidases. In this study, we have identified three lead compounds that selectively inhibit UL37-mediated protein deamidation, but not those mediated by cellular deamidases. Ground on these preliminary results, we will characterize the mode of action of these UL37 inhibitors in protein deamidation and innate immune response during HSV-1 infection. We will further employ a combination of mass spectrometry, structural and pharmacological analysis to improve these lead compounds via iterative synthesis and functional assays. The resulted best inhibitors will be assessed by pharmacokinetics and pharmacodynamic studies as well as antiviral efficacy using mouse model. This pilot study will not only provide proof-of-concept to counteract HSV-1 infection via inhibiting a viral deamidase and restoring host immune defense, but also develop important tools that enable further investigation into protein deamidation in fundamental biological processes.