| Institution: | 1. Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstr. 55, 38106 Braunschweig, Germany;2. School of Chemistry, National University of Ireland Galway, University Road, H91?TK33 Galway, Ireland;3. Department of Life Sciences and Chemistry, Jacobs University, Campus Ring 1, 28759 Bremen, Germany;4. Department of Chemistry, School of Life Sciences, University of Sussex, Falmer, BN1?9QJ Brighton, East Sussex, UK;5. Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France;6. Institut für Anorganische Chemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany;7. LCC–CNRS, Université de Toulouse, CNRS, UPS, Toulouse, France;8. Faculty of Chemistry, Department of Organic Chemistry, University of ?ód?, Tamka 12, 91-403 ?ód?, Poland;9. Department of Medicinal Chemistry and Fine Organic Synthesis, Lomonosov Moscow State University, Leninskie Gory 1/3, 119991 Moscow, Russia;10. Institute of Medical Virology, Universitätsklinikum Frankfurt, Paul-Ehrlich-Str. 40, 60596 Frankfurt, Germany |
| Abstract: | The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has called for an urgent need for dedicated antiviral therapeutics. Metal complexes are commonly underrepresented in compound libraries that are used for screening in drug discovery campaigns, however, there is growing evidence for their role in medicinal chemistry. Based on previous results, we have selected more than 100 structurally diverse metal complexes for profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike (S) protein with the ACE2 receptor and the papain-like protease PLpro. In addition to many well-established types of mononuclear experimental metallodrugs, the pool of compounds tested was extended to approved metal-based therapeutics such as silver sulfadiazine and thiomersal, as well as polyoxometalates (POMs). Among the mononuclear metal complexes, only a small number of active inhibitors of the S/ACE2 interaction was identified, with titanocene dichloride as the only strong inhibitor. However, among the gold and silver containing complexes many turned out to be very potent inhibitors of PLpro activity. Highly promising activity against both targets was noted for many POMs. Selected complexes were evaluated in antiviral SARS-CoV-2 assays confirming activity for gold complexes with N-heterocyclic carbene (NHC) or dithiocarbamato ligands, a silver NHC complex, titanocene dichloride as well as a POM compound. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents. |
