The protracted global COVID-19 pandemic urges the development of new drugs against the causative agent SARS-CoV-2. The clinically used glycopeptide antibiotic, teicoplanin, emerged as a potential antiviral, and its efficacy was improved with lipophilic modifications. This prompted us to prepare new lipophilic apocarotenoid conjugates of teicoplanin, its pseudoaglycone and the related ristocetin aglycone. Their antiviral effect was tested against SARS-CoV-2 in Vero E6 cells, using a cell viability assay and quantitative PCR of the viral RNA, confirming their micromolar inhibitory activity against viral replication. Interestingly, two of the parent apocarotenoids, bixin and β-apo-8'carotenoic acid, exerted remarkable anti-SARS-CoV-2 activity. Mechanistic studies involved cathepsin L and B, as well as the main protease 3CLPro, and the results were rationalized by computational studies. Glycopeptide conjugates show dual inhibitory action, while apocarotenoids have mostly cathepsin B and L affinity. Since teicoplanin is a marketed antibiotic and the natural bixin is an approved, cheap and widely used red colorant food additive, these readily available compounds and their conjugates as potential antivirals are worthy of further exploration.

Department of Biochemistry and Medical Chemistry Medical School University of Pécs Szigeti u 12 H 7624 Pécs Hungary

Department of Biotechnology Jožef Stefan Institute Jamova 39 1000 Ljubljana Slovenia

Department of Medical Microbiology Semmelweis University Nagyvárad tér 4 H 1089 Budapest Hungary

Department of Organic Chemistry University of Debrecen H 4032 Debrecen Hungary

Department of Pharmaceutical Chemistry University of Debrecen Egyetem tér 1 H 4032 Debrecen Hungary

Faculty of Pharmacy University of Ljubljana Aškerčeva cesta 7 1000 Ljubljana Slovenia

Institute of Biology Faculty of Sciences University of Pécs Ifjúság útja 6 H 7624 Pécs Hungary

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences Flemingovo nam 2 CZ 16000 Prague Czech Republic

Research Centre for Natural Sciences Medicinal Chemistry Research Group Magyar Tudósok krt 2 H 1117 Budapest Hungary

Szentágothai Research Centre National Laboratory of Virology Ifjúság útja 20 H 7624 Pécs Hungary

TargetEx Ltd Madách Imre Utca 31 2 H 2120 Dunakeszi Hungary

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Semisynthetic teicoplanin derivatives with dual antimicrobial activity against SARS-CoV-2 and multiresistant bacteria