Rational Design of Inhibitors of Poxviral RNA Polymerase

Poxviruses are large cytosolic DNA viruses with a propensity to cause zoonoses. They are present in animal reservoirs and responsible for a large spectrum of disorders, including human smallpox. Only few causative treatment options are available, but vaccination with the non-pathogenic vaccinia virus enabled the eradication of the smallpox-causing variola virus. However, the herd immunity against poxviruses is dwindling in humans. Accordingly, poxviruses including monkeypox virus are considered as potentially highly threatening for their pandemic ‘spillover’ risk. Here, we strive to develop novel virostatics for the fight of poxviral dieases. Our approach is based on a set of atomic resolution cryo EM structures of vaccinia transcription complexes that we have recently determined. We use in silico screening to identify novel binders, test them in a radionuclide transcription assay for inhibition and will characterize the resulting ligand-RNA polymerase complexes by cryo EM.