Antiviral Effect of 5′-Arylchalcogeno-3-aminothymidine Derivatives in SARS-CoV-2 Infection

The understanding that zidovudine (ZDV or azidothymidine, AZT) inhibits the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and that chalcogen atoms can increase the bioactivity and reduce the toxicity of AZT has directed our search for the discovery of novel potential anti-coronavirus compounds....

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Published in:	Molecules (Basel, Switzerland) Vol. 28; no. 18; p. 6696
Main Authors:	Tucci, Amanda Resende, da Rosa, Raquel Mello, Rosa, Alice Santos, Augusto Chaves, Otávio, Ferreira, Vivian Neuza Santos, Oliveira, Thamara Kelcya Fonseca, Coutinho Souza, Daniel Dias, Borba, Nathalia Roberto Resende, Dornelles, Luciano, Rocha, Nayra Salazar, Mayer, João Candido Pilar, da Rocha, João B. Teixeira, Rodrigues, Oscar Endrigo D, Miranda, Milene Dias
Format:	Journal Article
Language:	English
Published:	Basel MDPI AG 01-09-2023 MDPI
Subjects:	Antioxidants Atazanavir Calu-3 and Vero E6 Cell models Cancer therapies chalcogen-zidovudine Coronaviruses COVID-19 Cruz, Oswaldo Drugs Health aspects Infections NMR Nuclear magnetic resonance Pandemics Proteins Reverse transcriptase inhibitors RNA polymerase SARS-CoV-2 Selenium Severe acute respiratory syndrome coronavirus 2 tellurium Toxicity Viral infections viral replication Zidovudine Brazil
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Summary:	The understanding that zidovudine (ZDV or azidothymidine, AZT) inhibits the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and that chalcogen atoms can increase the bioactivity and reduce the toxicity of AZT has directed our search for the discovery of novel potential anti-coronavirus compounds. Here, the antiviral activity of selenium and tellurium containing AZT derivatives in human type II pneumocytes cell model (Calu-3) and monkey kidney cells (Vero E6) infected with SARS-CoV-2, and their toxic effects on these cells, was evaluated. Cell viability analysis revealed that organoselenium (R3a–R3e) showed lower cytotoxicity than organotellurium (R3f, R3n–R3q), with CC50 ≥ 100 µM. The R3b and R3e were particularly noteworthy for inhibiting viral replication in both cell models and showed better selectivity index. In Vero E6, the EC50 values for R3b and R3e were 2.97 ± 0.62 µM and 1.99 ± 0.42 µM, respectively, while in Calu-3, concentrations of 3.82 ± 1.42 µM and 1.92 ± 0.43 µM (24 h treatment) and 1.33 ± 0.35 µM and 2.31 ± 0.54 µM (48 h) were observed, respectively. The molecular docking calculations were carried out to main protease (Mpro), papain-like protease (PLpro), and RdRp following non-competitive, competitive, and allosteric inhibitory approaches. The in silico results suggested that the organoselenium is a potential non-competitive inhibitor of RdRp, interacting in the allosteric cavity located in the palm region. Overall, the cell-based results indicated that the chalcogen-zidovudine derivatives were more potent than AZT in inhibiting SARS-CoV-2 replication and that the compounds R3b and R3e play an important inhibitory role, expanding the knowledge about the promising therapeutic capacity of organoselenium against COVID-19.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work.
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules28186696