In Vivo Safety Assessment of AZT-derived Organochalcogen Compounds with Promising Antiviral Effects against SARS-Cov-2.

BACKGROUND

Developing new COVID-19 antivirals requires understanding viral proteins, oxidative stress, and drug repositioning. Safety assessments of organochalcogen molecules derived from AZT in Caenorhabditis elegans offer promising prospects for new treatments.

OBJECTIVE

In this work, we evaluated the safety and antioxidant effect of eight organochalcogen AZT-derivatives using the free-living nematode C. elegans through chronic exposure [48 h]. In addition, we used in silico computational modelling analyses to predict protein targets for these compounds.

METHODS

This study used survival, litter size, brood size as toxicological and safety parameters, subcellular localization of DAF-16, expression of SOD-3 and GST-4, and ROS levels to evaluate the antioxidant effects and target prediction by similarity set approach (SEA), protein-protein interaction (PPI) network analysis, and comparative phylogenetic analysis to predict protein targets for these compounds.

RESULTS

The molecules were safe at concentrations of 1-500 μM. AZT, R3a, and R3f promoted DAF-16 nuclear translocation without affecting SOD-3 levels. R3f reduced GST-4 levels, while R3a increased ROS levels. In silico analyses identified 16 human protein targets of AZT and its derivatives, linked to nucleotide metabolism, DNA replication, and anti-inflammatory pathways, showing high homology to C. elegans.

CONCLUSION

We hypothesize that Se and Te atom insertion may alter pharmacological properties by modulating DAF-16, GST-4, and ROS-related pathways. In silico data suggest these derivatives are promising for antiviral activity, targeting nucleotide metabolism and DNA replication while also potentially modulating the anti-inflammatory response, an appealing feature for COVID-19 treatment.