Genotoxicity assessment of potentially mutagenic nucleoside analogues using ToxTracker®.
Toxicol Lett
; 362: 50-58, 2022 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-35569722
ABSTRACT
Nucleoside analogues have long been designed and tested in cancer treatment and against viral infections. However, several early compounds were shown to have mutagenic properties as a consequence of their mode-of-action. This limited their use, and several have been discontinued for lengthy treatments or altogether. Nonetheless, nucleoside analogues remain an attractive modality for virally driven diseases, of which many still are without proper treatment options. To quantitatively assess the genotoxic mode-of-action of a panel of nucleoside analogues, we applied the ToxTracker® reporter assay. Many of the early nucleoside analogues showed a genotoxic response. The more recently developed nucleoside analogues, Remdesivir and Molnupiravir that are currently being repurposed for Covid-19 treatment, had a different profile in ToxTracker and did not induce the genotoxicity reporters. Our analyses support the metabolite GS-441524 over the parent analogue Remdesivir. In contrast, Molnupiravir was devoid of clear cellular toxicity while its active metabolite (EIDD-1931) was cytotoxic and induced several biomarkers. Nucleoside analogues continue to be attractive treatment options upon viral infections. ToxTracker readily distinguished between the genotoxic analogues and those with different profiles and provides a basis for clustering and potency ranking, offering a comprehensive tool to assess the toxicity of nucleoside analogues.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tratamento Farmacológico da COVID-19
/
Mutagênicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article