Available antiherpesvirus drugs target viral DNA polymerases. These drugs are usually highly effective, although toxicity and development of resistance limit their use. Derivatives of Spironolactone, an existing drug used to treat congestive heart failure, cirrhosis, and kidney problems, inhibit replication of Epstein-Barr virus (EBV), Kaposi’s sarcoma-associated herpesvirus (KSHV), and Herpes Simplex Virus (HSV). These derivatives exhibit decreased anti-mineralocorticoid activity and increased antiviral activity. The proposed therapeutic degrades cellular transcription factors related to virus production, lytic replication and gene expression. Use of this therapeutic has the potential to prevent KSHV and treat infectious mononucleosis, CMV, and HSV infections.