Triterpenoids manipulate a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral envelopes.
Longlong SiKun MengZhenyu TianJiaqi SunHuiqiang LiZiwei ZhangVeronica SolovevaHaiwei LiGe FuQing XiaSulong XiaoLihe ZhangDemin ZhouPublished in: Science advances (2018)
A trimer-of-hairpins motif has been identified in triggering virus-cell fusion within a variety of viral envelopes. Chemically manipulating such a motif represents current repertoire of viral fusion inhibitors. Here, we report that triterpenoids, a class of natural products, antagonize this trimer-of-hairpins via its constitutive heptad repeat-2 (HR2), a prevalent α-helical coil in class I viral fusion proteins. Triterpenoids inhibit the entry of Ebola, Marburg, HIV, and influenza A viruses with distinct structure-activity relationships. Specifically, triterpenoid probes capture the viral envelope via photocrosslinking HR2. Profiling the Ebola HR2-triterpenoid interactions using amino acid substitution, surface plasmon resonance, and nuclear magnetic resonance revealed six residues accessible to triterpenoids, leading to wrapping of the hydrophobic helix and blocking of the HR1-HR2 interaction critical in the trimer-of-hairpins formation. This finding was also observed in the envelopes of HIV and influenza A viruses and might potentially extend to a broader variety of viruses, providing a mechanistic insight into triterpenoid-mediated modulation of viral fusion.
Keyphrases
- sars cov
- magnetic resonance
- antiretroviral therapy
- single cell
- hiv infected
- human immunodeficiency virus
- hiv positive
- hepatitis c virus
- hiv aids
- hiv testing
- magnetic resonance imaging
- small molecule
- transcription factor
- men who have sex with men
- bone marrow
- computed tomography
- mesenchymal stem cells
- living cells
- genetic diversity
- aqueous solution