Metallodrug profiling against SARS-CoV-2 target proteins identifies highly potent inhibitors of the S/ACE2 interaction and the papain-like protease PL<sup>pro</sup>

Gil-Moles, Maria, Türck, Sebastian, Basu, Uttara, Pettenuzzo, Andrea, Bhattacharya, Saurav, Rajan, Ananthu, Ma, Xiang, Büssing, Rolf, Wölker, Jessica, Burmeister, Hilke, Kusi-Nimarko, Josephine, Hassell-Hart, Storm, McGown, Andrew, Guest, Daniel, Spencer, John and others, (2021) Metallodrug profiling against SARS-CoV-2 target proteins identifies highly potent inhibitors of the S/ACE2 interaction and the papain-like protease PL<sup>pro</sup>. Chemistry - A European Journal, 27 (71). pp. 17928-17940. ISSN 0947-6539

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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.

Item Type: Article
Keywords: PLpro, SARS-CoV-2, gold, metallodrugs, polyoxometalates, silver, spike protein, titanocene, Angiotensin-Converting Enzyme 2, Antiviral Agents, Coronavirus Papain-Like Proteases, SARS-CoV-2, Spike Glycoprotein, Coronavirus
Schools and Departments: School of Life Sciences > Chemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 10 Feb 2022 09:21
Last Modified: 03 Mar 2022 11:30
URI: http://sro.sussex.ac.uk/id/eprint/104293

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Project NameSussex Project NumberFunderFunder Ref
Satellite Bid for the Covid-19 Moonshot; High Throughput Synthesis and Xray Crystallography towards Novel Proease Inhibitors of Covid-19 (ISSF)G3091WELLCOME TRUSTUnset
UKRI C19 Extension Fund (Title: Poised Fragment Libraries for Atypical Bromodomain Inhibition)G3157UNIVERSITY OF SUSSEXUnset