tetano
Editor, Senior Moderator
Chemistry
. 2021 Oct 29.
doi: 10.1002/chem.202103258. Online ahead of print.
Metallodrug Profiling against SARS-CoV-2 Target Proteins Identifies Highly Potent Inhibitors of the Spike/ACE2 interaction and the Papain-like Protease PLpro
Maria Gil-Moles[SUP] 1 [/SUP], Sebastian Türck[SUP] 2 [/SUP], Uttara Basu[SUP] 3 [/SUP], Andrea Pettenuzzo[SUP] 4 [/SUP], Saurav Bhattacharya[SUP] 5 [/SUP], Ananthu Rajan[SUP] 5 [/SUP], Xiang Ma[SUP] 5 [/SUP], Rolf Büssing[SUP] 6 [/SUP], Jessica Wölker[SUP] 2 [/SUP], Hilke Burmeister[SUP] 2 [/SUP], Henrik Hoffmeister[SUP] 2 [/SUP], Pia Schneeberg[SUP] 2 [/SUP], Andre Prause[SUP] 2 [/SUP], Petra Lippmann[SUP] 1 [/SUP], Josephine Kusi-Nimarko[SUP] 7 [/SUP], Storm Hassell-Hart[SUP] 8 [/SUP], Andrew McGown[SUP] 7 [/SUP], Daniel Guest[SUP] 7 [/SUP], Yan Lin[SUP] 9 [/SUP], Anna Notaro[SUP] 9 [/SUP], Robin Vinck[SUP] 9 [/SUP], Johannes Karges[SUP] 9 [/SUP], Kevin Cariou[SUP] 9 [/SUP], Kun Peng[SUP] 10 [/SUP], Xue Qin[SUP] 11 [/SUP], Xin Wang[SUP] 11 [/SUP], Joanna Skiba[SUP] 12 [/SUP], Łukasz Szczupak[SUP] 12 [/SUP], Konrad Kowalski[SUP] 12 [/SUP], Ulrich Schatzschneider[SUP] 13 [/SUP], Catherine Hemmert[SUP] 14 [/SUP], Heinz Gornitzka[SUP] 14 [/SUP], Elena R Milaeva[SUP] 15 [/SUP], Alexey A Nazarov[SUP] 15 [/SUP], Gilles Gasser[SUP] 9 [/SUP], John Spencer[SUP] 7 [/SUP], Luca Ronconi[SUP] 4 [/SUP], Ulrich Kortz[SUP] 5 [/SUP], Jindrich Cinatl[SUP] 16 [/SUP], Denisa Bojkova[SUP] 16 [/SUP], Ingo Ott[SUP] 17 [/SUP]
Affiliations
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 the 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 a profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike protein with the ACE2 receptor and the papain-like protease PL pro . 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 spike/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 PL pro 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. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.
Keywords: gold, metallodrugs, PLpro, polyoxometalates, SARS-CoV-2, silver, spike protein, titanocene.
. 2021 Oct 29.
doi: 10.1002/chem.202103258. Online ahead of print.
Metallodrug Profiling against SARS-CoV-2 Target Proteins Identifies Highly Potent Inhibitors of the Spike/ACE2 interaction and the Papain-like Protease PLpro
Maria Gil-Moles[SUP] 1 [/SUP], Sebastian Türck[SUP] 2 [/SUP], Uttara Basu[SUP] 3 [/SUP], Andrea Pettenuzzo[SUP] 4 [/SUP], Saurav Bhattacharya[SUP] 5 [/SUP], Ananthu Rajan[SUP] 5 [/SUP], Xiang Ma[SUP] 5 [/SUP], Rolf Büssing[SUP] 6 [/SUP], Jessica Wölker[SUP] 2 [/SUP], Hilke Burmeister[SUP] 2 [/SUP], Henrik Hoffmeister[SUP] 2 [/SUP], Pia Schneeberg[SUP] 2 [/SUP], Andre Prause[SUP] 2 [/SUP], Petra Lippmann[SUP] 1 [/SUP], Josephine Kusi-Nimarko[SUP] 7 [/SUP], Storm Hassell-Hart[SUP] 8 [/SUP], Andrew McGown[SUP] 7 [/SUP], Daniel Guest[SUP] 7 [/SUP], Yan Lin[SUP] 9 [/SUP], Anna Notaro[SUP] 9 [/SUP], Robin Vinck[SUP] 9 [/SUP], Johannes Karges[SUP] 9 [/SUP], Kevin Cariou[SUP] 9 [/SUP], Kun Peng[SUP] 10 [/SUP], Xue Qin[SUP] 11 [/SUP], Xin Wang[SUP] 11 [/SUP], Joanna Skiba[SUP] 12 [/SUP], Łukasz Szczupak[SUP] 12 [/SUP], Konrad Kowalski[SUP] 12 [/SUP], Ulrich Schatzschneider[SUP] 13 [/SUP], Catherine Hemmert[SUP] 14 [/SUP], Heinz Gornitzka[SUP] 14 [/SUP], Elena R Milaeva[SUP] 15 [/SUP], Alexey A Nazarov[SUP] 15 [/SUP], Gilles Gasser[SUP] 9 [/SUP], John Spencer[SUP] 7 [/SUP], Luca Ronconi[SUP] 4 [/SUP], Ulrich Kortz[SUP] 5 [/SUP], Jindrich Cinatl[SUP] 16 [/SUP], Denisa Bojkova[SUP] 16 [/SUP], Ingo Ott[SUP] 17 [/SUP]
Affiliations
- PMID: 34714566
- DOI: 10.1002/chem.202103258
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 the 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 a profiling as inhibitors of two relevant SARS-CoV-2 replication mechanisms, namely the interaction of the spike protein with the ACE2 receptor and the papain-like protease PL pro . 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 spike/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 PL pro 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. These studies might provide starting points for the design of metal-based SARS-CoV-2 antiviral agents.
Keywords: gold, metallodrugs, PLpro, polyoxometalates, SARS-CoV-2, silver, spike protein, titanocene.