Multiformin-Type Azaphilones Prevent SARS-CoV-2 Binding to ACE2 Receptor.

Protein microarray screenings identified fungal natural products from the azaphilone family as potent inhibitors of SARS-CoV-2 spike protein binding to host ACE2 receptors. Cohaerin F, as the most potent substance from the cohaerin group, led to more than 50% less binding of ACE2 and SARS-CoV-2 spike protein. A survey for structurally related azaphilones yielded the structure elucidation of six new multiformins E-J ( 10 - 15 ) and the revision of the stereochemistry of the multiformins. Cohaerin and multiformin azaphilones (1-5, 8 , 12 ) were assessed for their activity in a cell-based infection assay. Calu-3 cells expressing human ACE2 receptor showed more than 75% and 50% less infection by SARS-CoV-2 pseudotyped lentivirus particles after treatment with cohaerin C (1) and cohaerin F ( 4 ), respectively. Multiformin C ( 8 ) and G ( 12 ) that nearly abolished the infection of cells. Our data show that multiformin-type azaphilones prevent the binding of SARS-CoV-2 to the cell entry receptor ACE2.