Diazadispiroalkane derivatives - new viral entry inhibitors

Adfeldt, Rebekka; Schmitz, Janna; Kropff, Barbara; Thomas, Marco ORCID; Monakhova, Natalia; Hölper, Julia E. GND; Klupp, Barbara GND; Mettenleiter, Thomas C. GND; Makarov, Vadim; Bogner, Elke ORCID

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. In this study, we characterized the antiviral activity of two new diazadispiroalkane derivatives, 11826091 and 11826236. These two small molecules exhibited strong activity against low-passage HCMV. Pre-treatment of cell-free virus with these compounds greatly reduced infection. 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 of infection. Interestingly, 11826236 had an effect by addition to cells after infection. Results from entry assays showed the major effect on attachment. Only 11826236 has a minimal effect on penetration comparable to Heparin. Further, no effect on virus infection was found for cell lines with a defect in heparan sulfate expression or lacking all surface glycosaminoglycans indicating that these small molecules bind to heparan sulfate on the cell surface. 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.

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Adfeldt, Rebekka / Schmitz, Janna / Kropff, Barbara / et al: Diazadispiroalkane derivatives - new viral entry inhibitors. 2021.

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