Chemistry A European J - 2021 - Gil%E2%80%90Moles - Metallodrug Profiling against SARS%E2%80%90CoV%E2%80%902 Target Proteins Identifies Highly.pdf (6.34 MB)
Metallodrug profiling against SARS-CoV-2 target proteins identifies highly potent inhibitors of the S/ACE2 interaction and the papain-like protease PLpro
journal contribution
posted on 2023-06-15, 20:37 authored by Maria Gil-Moles, Sebastian Türck, Uttara Basu, Andrea Pettenuzzo, Saurav Bhattacharya, Ananthu Rajan, Xiang Ma, Rolf Büssing, Jessica Wölker, Hilke Burmeister, Josephine Kusi-Nimarko, Storm Hassell-HartStorm Hassell-Hart, Andrew McGownAndrew McGown, Daniel GuestDaniel Guest, John SpencerJohn Spencer, othersThe 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.
Funding
Satellite Bid for the Covid-19 Moonshot; High Throughput Synthesis and Xray Crystallography towards Novel Proease Inhibitors of Covid-19 (ISSF); G3091; WELLCOME TRUST
UKRI C19 Extension Fund (Title: Poised Fragment Libraries for Atypical Bromodomain Inhibition); G3157; UNIVERSITY OF SUSSEX
History
Publication status
- Published
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- Published version
Journal
Chemistry - A European JournalISSN
0947-6539Publisher
WileyExternal DOI
Issue
71Volume
27Page range
17928-17940Event location
GermanyDepartment affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-02-10First Open Access (FOA) Date
2022-02-10First Compliant Deposit (FCD) Date
2022-02-10Usage metrics
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