Tenofovir Disoproxil Fumarate: New Chemical Developments and Encouraging in vitro Biological Results for SARS-CoV-2

Clososki, Giuliano C.; Soldi, Rafael A.; Silva, Rodrigo M. da; Guaratini, Thais; Lopes, José N. C.; Pereira, Pamela R. R.; Lopes, João Luís Callegari; Santos, Thiago dos; Martins, Ronaldo B.; Costa, Carolina Ortiz Rocha da; Carvalho, Andreia N. de; daSilva, Luis L. P.; Arruda, Eurico; Lopes, Norberto P.

doi:10.21577/0103-5053.20200106

Cited by 31 publications

(40 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Consistent with our findings, tenofovirdiphosphate has been shown to permanently terminate polymerase extension of nascent RNA when using recombinant RdRp-CoV2 [25]. However, infusion of tenofovir in Vero cell cultures did not inhibit replication of SARS-CoV-2 [26,27], while the use of 3-90 μM of its prodrug TDF yielded a 15-fold reduction of viral genome release [26] . Further, the use of TDF/FTC for treating SARS-CoV-2 infected ferrets led to better clinical scores and lower virus titers in nasal washes compared to a placebo [28].…”

Section: Discussionsupporting

confidence: 88%

Tenofovir and remdesivir ensemble docking with the SARS-CoV-2 polymerase and template-nascent RNA

Salazar

Ramos

Cruz

et al. 2020

Preprint

View full text Add to dashboard Cite

Repositioning of remdesivir and tenofovir against COVID-19 has shown only partial evidence of improving clinical outcomes, in clinical trials and observational studies respectively. The rationale behind this inconsistent efficacy remains unknown. Here, we developed an ensemble docking approach for the active triphosphate forms of both antivirals with the SARS-CoV-2 polymerase and the RNA chain complex, under the hypothesis that clinical observation could rely on the specificities of the drug-target interaction. Our model framework allowed accurate reconstruction of the remdesivir ensemble, which presented the strongest binding affinity and pose stability close to the natural counterpart dATP. We further observed a set of features of the tenofovir complex that suggests functional yet suboptimal interaction, likely resulting in limited viral inhibition in the absence of high intracellular concentration at target tissues. Our findings provide rationale for the mixed effectiveness of tenofovirbased compounds against SARS-CoV-2 and underscore the relevance of the intracellular availability of the nucleotide analogues relative to viral tropism.

show abstract

Section: Discussionsupporting

confidence: 88%

Tenofovir and remdesivir ensemble docking with the SARS-CoV-2 polymerase and template-nascent RNA

Salazar

Ramos

Cruz

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…To investigate this hypothesis, we treated SARS-CoV-2–exposed neutrophils with tenofovir disoproxil fumarate (TDF), an inhibitor of RNA polymerase that has been shown to reduce SARS-CoV-2 replication in Vero cells ( Elfiky, 2020 ; Clososki et al, 2020 ). TDF is a drug of the same class of remdesivir, which is effective in vitro against virus replication and accelerates the recovery of COVID-19 patients ( Yin et al, 2020 ; Beigel et al, 2020 ).…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2–triggered neutrophil extracellular traps mediate COVID-19 pathology

Veras

Pontelli

Silva

et al. 2020

Journal of Experimental Medicine

Self Cite

717

787

View full text Add to dashboard Cite

Severe COVID-19 patients develop acute respiratory distress syndrome that may progress to cytokine storm syndrome, organ dysfunction, and death. Considering that neutrophil extracellular traps (NETs) have been described as important mediators of tissue damage in inflammatory diseases, we investigated whether NETs would be involved in COVID-19 pathophysiology. A cohort of 32 hospitalized patients with a confirmed diagnosis of COVID-19 and healthy controls were enrolled. The concentration of NETs was augmented in plasma, tracheal aspirate, and lung autopsies tissues from COVID-19 patients, and their neutrophils released higher levels of NETs. Notably, we found that viable SARS-CoV-2 can directly induce the release of NETs by healthy neutrophils. Mechanistically, NETs triggered by SARS-CoV-2 depend on angiotensin-converting enzyme 2, serine protease, virus replication, and PAD-4. Finally, NETs released by SARS-CoV-2–activated neutrophils promote lung epithelial cell death in vitro. These results unravel a possible detrimental role of NETs in the pathophysiology of COVID-19. Therefore, the inhibition of NETs represents a potential therapeutic target for COVID-19.

show abstract

“…Probably due to the sample size, we cannot see significant results in this regard. Nevertheless, several authors have described the potential activity of tenofovir in SARS-CoV-2 [39] , [40] and specific studies are required to answer this question.…”

Section: Discussionmentioning

confidence: 99%