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 [48h]. 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.