publication . Article . 2021

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; Sebastian Türck; Uttara Basu; Andrea Pettenuzzo; Saurav Bhattacharya; Ananthu Rajan; Xiang Ma; Rolf Büssing; Jessica Wölker; Hilke Burmeister; ...
Open Access English
  • Published: 29 Oct 2021
  • Publisher: HAL CCSD
  • Country: France
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.
Despite their increasing relevance in medicinal chemistry, metal complexes are still underrepresented in compound screening libraries for drug discovery. In this work more than 100 metal complexes were evaluated as inhibitors of two targets in the SARS‐CoV‐2 life cycle, the interaction of the spike protein with the ACE2 receptor and the protease PLpro. The most active inhibitors were studied for antiviral effects in SARS‐CoV‐2 infected cells and led to the discovery of active compounds that will provide starting points for future drug design.
Persistent Identifiers
free text keywords: gold, metallodrugs, PL pro, polyoxometalates, SARS-CoV-2, silver, spike protein, titanocene, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, General Chemistry, Catalysis, Organic Chemistry, Full Paper, Full Papers, gold, metallodrugs, PLpro, Receptor, Papain, chemistry.chemical_compound, chemistry, Protease, medicine.medical_treatment, medicine, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Spike Protein, Strong inhibitor, Combinatorial chemistry, Titanocene dichloride, Drug discovery
  • COVID-19
Funded by
EC| PhotoMedMet
Towards Novel Inert (Photo-)toxic Ru(II) Polypyridyl Complexes
  • Funder: European Commission (EC)
  • Project Code: 681679
  • Funding stream: H2020 | ERC | ERC-COG
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