Identification of natural products for blocking Kaposi’s sarcoma-associated herpesvirus entry and primary infection

Approximately 20% of human cancers have been attributed to virus infections, including Kaposi’s sarcoma-associated herpesvirus (KSHV), which can cause several human cancers arising in immunocompromised patients. KSHV can also establish lifelong infection in immunocompetent individuals. The prevalence of KSHV infection is high in HIV-endemic regions, such as sub-Saharan Africa, as well as in certain subpopulations, including men who have sex with men (MSM) and organ transplant recipients. Prevention of primary KSHV infection is important for reducing the incidence of these virus-associated malignancies, especially in high-risk populations; however, no drugs or vaccines are currently available for this purpose. In the current study, we identified three tannin-related compounds displaying prominent antiviral activity against primary KSHV infection through screening of a natural compound library. Remarkably, the inhibitory effects of these natural compounds were completely independent of cytotoxicity and showed high specificity for KSHV. Furthermore, we found that these compounds effectively blocked KSHV entry by interfering with viral attachment to host cells. Using both in vitro and in silico analyses, we demonstrated that these tannin-related compounds interfered with the interaction between EphA2 and KSHV gH/gL by competitively binding to the viral glycoproteins, the details of compound-protein interaction, including those key residues and mutation analysis. Together, these findings demonstrate that tannin-related compounds are promising anti-KSHV agents with the potential to reduce the incidence of KSHV-related diseases.