In silico evidences of Mpro inhibition by a series of organochalcogen-AZT derivatives and their safety in Caenorhabditis elegans

In silico evidences of Mpro inhibition by a series of organochalcogen-AZT derivatives and their safety in Caenorhabditis elegans

The new coronavirus (SARS-CoV-2) pandemic emerged in 2019 causing millions of deaths. Vaccines were quickly developed and made available in 2021. Despite the availability of vaccines, some subjects refuse to take the immunizing or present comorbities, therefore developing serious cases of COVID-19,...

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Published in:Journal of trace elements in medicine and biology Vol. 80; p. 127297
Main Authors: Viçozzi, Gabriel Pedroso, de Oliveira Pereira, Flávia Suelen, da Silva, Rafael Santos, Leal, Julliano Guerin, Sarturi, Joelma Menegazzi, Nogara, Pablo Andrei, Rodrigues, Oscar Endrigo Dorneles, Teixeira da Rocha, João Batista, Ávila, Daiana Silva
Format: Journal Article
Language:English
Published: Elsevier GmbH 01-12-2023
Subjects:
Alternative model
Antioxidant
SARS-CoV-2
Selenium
Sulfur
Tellurium
δ-ALA-D
GST-4
Mn
DMSO
NaOH
CDNB
H2O2
Tris-HCl
Tellurium
E.coli OP50
PDB
GFP
Te
SARS-CoV-2
ANOVA
SH
RdRp
Z1
TFK
Z2
Z3
Selenium
Sulfur
GSH
NaOCl
CGC
WHO
FOXO
gcs-1
C. elegans
SDS
Alternative model
DTNB
Mpro
EDTA
Antioxidant
DEM
PBMCs
SKN-1
Se
HIV
NGM
DAF-16
ROS
NaCl
SOD-3
DCF-DA
AZT
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Summary:The new coronavirus (SARS-CoV-2) pandemic emerged in 2019 causing millions of deaths. Vaccines were quickly developed and made available in 2021. Despite the availability of vaccines, some subjects refuse to take the immunizing or present comorbities, therefore developing serious cases of COVID-19, which makes necessary the development of antiviral drugs. Previous studies have demonstrated that ebselen, a selenium-containing molecule, can inhibit SARS-CoV-2 Mpro. In addition, selenium is a trace element that has antiviral and anti-inflammatory properties. Zidovudine (AZT) has been widely used against HIV infections and its action against SARS-CoV-2 may be altered by the structural modification with organochalcogen moieties, but this hypothesis still needs to be tested. In the present work we evaluated the Mpro inhibition capacity (in silico), the safety and antioxidant effect of six organochalcogen AZT-derivatives using the free-living nematode Caenorhabditis elegans, through acute (30 min) and chronic (48) exposure protocols. We observed that the molecules were safe at a concentration range of 1–500 µM and did not alter any toxicological endpoint evaluated. Furthermore, the molecules are capable to decrease the ROS formation stimulated by hydrogen peroxide, to modulate the expression of important antioxidant enzymes such superoxide-dismutase-3 and glutathione S-transferese-4 and to stimulate the translocation of the DAF-16 to the cell nucleus. In addition, the molecules did not deplete thiol groups, which reinforces their safety and contribution to oxidative stress resistance. We have found that compounds S116l (a Tellurium AZT-derivative) and S116h (a Selenium-AZT derivative) presented more promising effects both in silico and in vivo, being strong candidates for further in vivo studies.
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ISSN:0946-672X
1878-3252
DOI:10.1016/j.jtemb.2023.127297