Síntesis de nucleósidos y su evaluación biológica como inhibidores selectivos de la retrotransposición de LINE-1 de mamíferos

Résumé

ABSTRACT Long interspersed element class 1 (LINE-1 or L1) is the only active autonomous transposable element in humans. It comprises 17% of our genomic mass, although most L1 copies are inactive due to mutations and rearrangements. However, an average human genome contains 80-100 active L1s, and their mobilization continue to impacts our genome. L1s move by a copy and paste mechanism that involves the reverse transcription of an intermediate L1 RNA. In humans, L1 mobilization during early embryogenesis led to the accumulation of heritable insertions that sporadically can be mutagenic and generate a genetic disorder. Surprisingly, L1s are also active in cancer cells and the human brain, impacting our somatic genome. L1 elements are frequently overexpressed in human tumors, and the accumulation of new insertions can potentially increase the malignancy and metastasis potential of tumor cells. Thus, although the role of somatic retrotransposition is currently unknown, it has the potential to influence cancer origin and progression, as well as brain biology. To learn more on the role of L1 activity in cancer cells and the brain, Loss of Function (LOF) strategies will be very informative. Here, and to explore whether inhibition of the Reverse Transcriptase of L1 can be used as an effective LOF strategy, we tested currently available and de novo synthesized nucleoside related compounds as selective L1 inhibitors. After analysing 33 nucleoside structures using an L1 retrotransposition assay, we identified three non-toxic selective L1 inhibitors that exhibit no activity against other retroelements (LTR-containing retrotransposons). Notably, these compounds can efficiently inhibit human and mouse LINE-1s, and could be used to determine the impact of L1 activity in mouse models, in a LOF approach. Importantly, these compounds also have the potential to be effective in the treatment of those cancers characterized by a high L1 expression.