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

Identification of a Thyroid Hormone Binding Site in Hsp90 with Implications for Its Interaction with Thyroid Hormone Receptor Beta

While many proteins are known clients of heat shock protein 90 (Hsp90), it is unclear whether the transcription factor, thyroid hormone receptor beta (TRb), interacts with Hsp90 to control hormonal perception and signaling. Higher Hsp90 expression in mouse fibroblasts was elicited by the addition of triiodothyronine (T3). T3 bound to Hsp90 and enhanced adenosine triphosphate (ATP) binding of Hsp90 due to a specific binding site for T3, as identified by molecular docking experiments. The binding of TRb to Hsp90 was prevented by T3 or by the thyroid mimetic sobetirome. Purified recombinant TRb trapped Hsp90 from cell lysate or purified Hsp90 in pull-down experiments. The affinity of Hsp90 for TRb was 124 nM. Furthermore, T3 induced the release of bound TRb from Hsp90, which was shown by streptavidin-conjugated quantum dot (SAv-QD) masking assay. The data indicate that the T3 interaction with TRb and Hsp90 may be an amplifier of the cellular stress response by blocking Hsp90 activity

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

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

Identification of a Thyroid Hormone Binding Site in Hsp90 with Implications for Its Interaction with Thyroid Hormone Receptor Beta

While many proteins are known clients of heat shock protein 90 (Hsp90), it is unclear whether the transcription factor, thyroid hormone receptor beta (TRb), interacts with Hsp90 to control hormonal perception and signaling. Higher Hsp90 expression in mouse fibroblasts was elicited by the addition of triiodothyronine (T3). T3 bound to Hsp90 and enhanced adenosine triphosphate (ATP) binding of Hsp90 due to a specific binding site for T3, as identified by molecular docking experiments. The binding of TRb to Hsp90 was prevented by T3 or by the thyroid mimetic sobetirome. Purified recombinant TRb trapped Hsp90 from cell lysate or purified Hsp90 in pull-down experiments. The affinity of Hsp90 for TRb was 124 nM. Furthermore, T3 induced the release of bound TRb from Hsp90, which was shown by streptavidin-conjugated quantum dot (SAv-QD) masking assay. The data indicate that the T3 interaction with TRb and Hsp90 may be an amplifier of the cellular stress response by blocking Hsp90 activity