2. Academic Validation
  3. Modified (2'-deoxy)adenosines activate autophagy primarily through AMPK/ULK1-dependent pathway

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.
Ekaterina A Guseva 1,  Polina N Kamzeeva 2,  Sofya Y Sokolskaya 3,  Georgy K Slushko 2,  Evgeny S Belyaev 4,  Boris P Myasnikov 5,  Julia A Golubeva 6,  Vera A Alferova 7,  Petr V Sergiev 6,  Andrey V Aralov 8
Affiliations

Affiliations

  • 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: eguseva98@mail.ru.
  • 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: Baruh238@mail.ru.
PMID: 39362474 DOI: 10.1016/j.bmcl.2024.129980
Abstract

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.

Keywords

Adenosine; Autophagy; DNA lesion; Phosphate; Prodrug; RNA lesion.

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  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-168507
    Autophagy Activator