The development of broad-acting, host-targeting antivirals against emerging viruses
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Citation
Abstract
Emerging and reemerging RNA viruses constitute a major burden on public health. Their epidemic and pandemic potential, coupled with their ability to cause high mortality rates, drives the need for potent, broad-acting antiviral inhibitors of disease. These viruses include Ebola virus, which causes deadly hemorrhagic fever but is generally confined to smaller outbreaks, and SARS-CoV-2, which causes respiratory tract infection and has led to millions of hospitalizations and deaths during the recent pandemic. Due to their reliance on cellular factors for replication, targeting host cell pathways through small molecule inhibitors is an appealing approach to finding broadly acting antivirals. By generating host-targeting small molecule inhibitors that act potently against the replication cycle of many viruses, current outbreaks can be curbed, and future pandemics can be prevented. In this work, we described the development of two host-targeting, natural product small molecule inhibitors with distinct mechanisms: diphyllin, an entry inhibitor, and rocaglates, which are inhibitors of translation. We generated high-throughput screening methods to effectively screen hundreds of small molecule derivatives for inhibition of SARS-CoV-2 and Ebola virus replication and show low nanomolar potency for multiple compounds in immortalized, primary, and iPSC-derived cells. For each compound, we identified targets relevant to virus replication: The a2 subunit of the V-ATPase for diphyllin, and eIF4A, an RNA helicase, for rocaglates. For diphyllin, we explored host-virus interactions through the knock-out of relevant host factors in the context of virus infection. For rocaglates, we generated virus resistant to treatment through serial passaging and found changes in NSP1, a viral protein responsible for inhibiting host translation. Collectively, we generated strong in vitro antiviral profiles and host-virus interaction studies for the candidacy of diphyllin and rocaglates as broad-acting antivirals against RNA viruses with epidemic and pandemic potential.
Description
2025