N-arylpyrimidinamine (NAPA) compounds are broadly acting inhibitors of human cytomegalovirus infection and spread

Abstract

Human cytomegalovirus (HCMV) is a β-herpesvirus that contributes to the disease burden of immunocompromised and immunomodulated individuals, including transplant recipients and newborns. The FDA-approved HCMV drugs can exhibit drug resistance and severe side effects including bone marrow toxicity, gastrointestinal disruption, and nephrotoxicity. In a previous study, we identified the N-arylpyrimidinamine (NAPA) compound series as a new class of HCMV inhibitors that target early stages of infection. Here we describe the inhibitory activity of two potent NAPA analogs, MBXC-4336 and MBX-4992, that broadly block infection and spread. MBXC-4336 and MBX-4992 effectively inhibited infection by diverse HCMV strains and significantly prevented virus spread in fibroblast and epithelial cells as evaluated by quantifying infected cells and viral genome levels. Further, the NAPA compounds limited replication of clinical HCMV isolates, including a ganciclovir-resistant strain. Importantly, combination studies of NAPA compounds with ganciclovir demonstrated additive or synergistic inhibition of HCMV spread. Collectively, NAPA compounds have therapeutic potential for development as a novel class of anti-HCMV drugs.

Keywords: Broad spectrum antivirals; Combination therapy; Human cytomegalovirus; NAPA compounds; Synergy.