Modified (2'-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway
- Bioorg Med Chem Lett. 2024 Nov 15:113:129980. doi: 10.1016/j.bmcl.2024.129980.
- 1. Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia. Electronic address: [email protected].
- 2. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
- 3. Faculty of Fundamental Medicine, Lomonosov Moscow State University, 119991 Moscow, Russia.
- 4. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Science, 119071 Moscow, Russia.
- 5. Lomonosov Institute of Fine Chemical Technologies, MIREA-Russian Technological University, 119571 Moscow, Russia.
- 6. Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, 143025 Skolkovo, Russia; Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia.
- 7. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia.
- 8. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117997 Moscow, Russia; RUDN University, 117198 Moscow, Russia. Electronic address: [email protected].
Autophagy is a conserved self-digestion process, which governs regulated degradation of cellular components. Autophagy is upregulated upon energy shortage sensed by AMP-dependent protein kinase (AMPK). Autophagy activators might be contemplated as therapies for metabolic neurodegenerative diseases and obesity, as well as Cancer, considering tumor-suppressive functions of Autophagy. Among them, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr), a nucleoside precursor of the active phosphorylated AMP analog, is the most commonly used pharmacological modulator of AMPK activity, despite its multiple reported "off-target" effects. Here, we assessed the Autophagy/Mitophagy activation ability of a small set of (2'-deoxy)adenosine derivatives and analogs using a fluorescent reporter assay and immunoblotting analysis. The first two leader compounds, 7,8-dihydro-8-oxo-2'-deoxyadenosine and -adenosine, are nucleoside forms of major oxidative DNA and RNA lesions. The third, a derivative of inactive N6-methyladenosine with a metabolizable phosphate-masking group, exhibited the highest activity in the series. These compounds primarily contributed to the activation of AMPK and outperformed AICAr; however, retaining the activity in knockout cell lines for AMPK (ΔAMPK) and its upstream regulator SIRT1 (ΔSIRT1) suggests that AMPK is not a main cellular target. Overall, we confirmed the prospects of searching for Autophagy activators among (2'-deoxy)adenosine derivatives and demonstrated the applicability of the phosphate-masking strategy for increasing their efficacy.