Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Microbiology, Pharmacology & Pharmacy, POSTTRANSPLANT LYMPHOPROLIFERATIVE DISORDER, RESISTANT HERPES-SIMPLEX, ACYCLOVIR-RESISTANT, GENOTYPIC CHARACTERIZATION, ANTIVIRAL PROPHYLAXIS, DNA-POLYMERASE, VIRUS, EBV, INFECTION, MUTANTS, Animals, Antiviral Agents, Drug Resistance, Viral, Enzyme Assays, HeLa Cells, Herpesviridae Infections, Herpesvirus 1, Human, Herpesvirus 2, Human, Herpesvirus 3, Human, Herpesvirus 4, Human, Host-Pathogen Interactions, Humans, Mice, Mutation, NIH 3T3 Cells, Phosphorylation, Thionucleosides, Thiophenes, Thymidine, Thymidine Kinase, Viral Proteins, Hela Cells, 0605 Microbiology, 1108 Medical Microbiology, 1115 Pharmacology and Pharmaceutical Sciences, 3107 Microbiology, 3207 Medical microbiology, 3214 Pharmacology and pharmaceutical sciences

Abstract:

The emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivity in vitro. While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.