2021 ESMED General Assembly - Diazadispiroalkane derivatives - new viral entry inhibitors

Diazadispiroalkane derivatives - new viral entry inhibitors By Dr. Elke Prof. Dr. Bogner, Charité-Universitätsmedizin Berlin, Institute of Virology Abstract: Herpesviruses are widespread and can cause serious illness. Many currently available antiviral drugs have limited effects, result in rapid development of resistance and often exhibit dose-dependent toxicity. Especially for human cytomegalovirus (HCMV) new well-tolerated compounds with novel mechanisms of action are urgently needed. We investigated the antiviral effect of two small molecules (11826091 and 11826236) on HCMV infected human embryonic lung fibroblasts. Both substances were well tolerated and exhibited a strong dose dependent antiviral activity. Time of addition assays where 11826091 or 11826236 was added to cells before, before and during, during or after infection demonstrated an inhibitory effect on early steps Interestingly, 11826236 had an effect by addition to cells after infection. Detailed studies revealed that both small molecules block virus attachment but not penetration. Furthermore, the data suggest that these molecules cover the cell surface by binding to heparan sulfate thereby interfering with initial attachment. To test this further we extended our analyses to pseudorabies virus (PrV), a member of the Alphaherpesvirinae, which is known to use cell surface heparan sulfate for initial attachment via nonessential glycoprotein C (gC). While infection with PrV wild type was strongly impaired by 11826091 or 11826236 as with heparin, a mutant lacking gC was unaffected by either treatment demonstrating that primary attachment to heparan sulfate via gC is targeted by these small molecules. In summary, we demonstrate the high potency of 11826091 and 11826236 as new herpesvirus entry inhibitors. More details will be at 2021 ESMED General Assembly For more see Facebook of ESMED General Assembly and Youtube of European Society of Medicine

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