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Metallodrug Profiling against SARS‐CoV‐2 Target Proteins Identifies Highly Potent Inhibitors of the S/ACE2 interaction and the Papain‐like Protease PL pro
Author(s) -
GilMoles Maria,
Türck Sebastian,
Basu Uttara,
Pettenuzzo Andrea,
Bhattacharya Saurav,
Rajan Ananthu,
Ma Xiang,
Büssing Rolf,
Wölker Jessica,
Burmeister Hilke,
Hoffmeister Henrik,
Schneeberg Pia,
Prause Andre,
Lippmann Petra,
KusiNimarko Josephine,
HassellHart Storm,
McGown Andrew,
Guest Daniel,
Lin Yan,
Notaro Anna,
Vinck Robin,
Karges Johannes,
Cariou Kevin,
Peng Kun,
Qin Xue,
Wang Xing,
Skiba Joanna,
Szczupak Łukasz,
Kowalski Konrad,
Schatzschneider Ulrich,
Hemmert Catherine,
Gornitzka Heinz,
Milaeva Elena R.,
Nazarov Alexey A.,
Gasser Gilles,
Spencer John,
Ronconi Luca,
Kortz Ulrich,
Cinatl Jindrich,
Bojkova Denisa,
Ott Ingo
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202103258
Subject(s) - chemistry , papain , protease , covid-19 , drug discovery , combinatorial chemistry , biochemistry , virology , enzyme , biology , medicine , infectious disease (medical specialty) , disease , pathology
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 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 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 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 compound. These studies might provide starting points for the design of metal‐based SARS‐CoV‐2 antiviral agents.