| Congresso Brasileiro de Microbiologia 2023 | Resumo: 1182-1 | ||||
Resumo:COVID-19, caused by the highly pathogenic SARS-CoV-2, is considered a major global public health problem. Many efforts have been directed to search for antiviral drugs. However, clinical studies have shown limited or nonexistent efficacy for most proposed medications. An important trend in the chemotherapy field involves the study of nucleoside analogs and the analysis of their multiple antioxidant, antitumor, antimicrobial, and antiviral properties. The understanding that zidovudine (AZT) inhibits the RNA-dependent RNA polymerase of SARS-CoV-2 (RdRp) and that chalcogen atoms can increase the bioactivity and reduce the toxicity of AZT has directed our search for anti-coronavirus compounds. Here we evaluated the antiviral activity of selenium and tellurium containing AZT derivatives in human type II pneumocytes (Calu-3) and monkey kidney cells (Vero E6) infected with SARS-CoV-2, and their toxic effects on both cell lines. Cell viability analysis revealed that organoselenium (R3a – R3e) showed lower cytotoxicity than organotellurium compounds (R3f, R3n – R3q), with CC50 ≥ 100 μM. The R3b and R3e compounds 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 μM and 1.99 μM, respectively, while in Calu-3, concentrations of 3.82 μM and 1.9 μM (24h treatment) and 1.33 μM and 2.31 μM (48h treatment) were observed. The molecular docking assays suggest that R3a-R3e can bind to SARS-CoV-2 major protease active site. These findings revealed that R3b and R3e play an important inhibitory role in the replication of SARS-CoV-2 in vitro and expand knowledge about the role of organoselenium as a promising therapeutic agent against COVID-19. This set of data prospects chalcogen-zidovudine compounds and motivates us to study another possible mechanism of action. Therefore, the question arises as to whether the replicative SARS-CoV-2 inhibition may be the result of a dual action of AZT derivatives with selenium. These compounds could act in viral proteases and polymerase or interact with only one target of the novel coronavirus.
Palavras-chave: Chalcogens, Human pneumocytes, SARS-CoV-2, Viral replication, Zidovudine Agência de fomento:CNPq, CAPES, IOC-FIOCRUZ, FAPERJ | |||||