Mechanism of Anti -Herpes simplex Virus Type-1 Activity of Two Novel Small Molecules

Background and Objectives: The problem of drug-resistant strains has grown as a global concern, so it is necessary to develop new strategies to get rid of HSV infections in humans. Inspired by history, natural products have been the most prosperous source of new drugs, particularly as anticancer and antimicrobial agents. Compounds with specific mechanisms of action have played a pivotal role in many drug development and research programs. In this study, to further understand the effect of Triptolide and (S)-10-Hydroxycamptothecin on the HSV replication cycle, DNA levels in the absence or presence of these compounds during 24 hour post-infection (h.p.i) and mRNA levels of HSV-1 Immediate Early, Early and Late genes in the absence or presence of these compounds during 24 hour post-infection (h.p.i) were investigated. Materials and Methods: Viral infectivity during different steps of HSV-1 replication cycle on A549 cells was evaluated with different assays including; adsorption inhibition assay, penetration inhibition assay, time-of-addition assay, quantitative polymerase chain reaction (qPCR) to investigate DNA and mRNA level. Results: The results showed that Triptolide can inhibit virus adsorption and penetration, compared to 10-Hydroxycamptothecin and controls. Moreover, time-of-addition further suggested that Triptolide and (S)-10-Hydroxycamptothecin has viral inhibitory effects when added up to 6 h and up to 8 h post-infection (h.p.i.), respectively. Also, expression of the ICP27, ICP 4, and ICP 22 protein was strongly inhibited in the Triptolide- treated group, which may indicate that the formation of HSV replication compartments was impeded. Conclusion: As revealed, the problem of drug-resistant strains has grown as a global concern, so it seems necessary to develop new strategies to get rid of HSV infections in humans. This study showed that the antiviral activities of Triptolide and (S)-10-hydroxycamptothecin were less than cytotoxic concentrations and have dose-dependent manner, suggesting that they were mediated by a specific mechanism and not by cytotoxicity. Conclusively, this report offers new perspectives in the search for therapeutic measures in the treatment of HSV-1 infection.