Double-modified, thio and methylene ATP analogue facilitates wound healing in vitro and in vivo.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Wound Healing*/drug effects ; Adenosine Triphosphate*/metabolism ; Keratinocytes*/drug effects ; Keratinocytes*/metabolism ; Zebrafish*; Humans ; Animals ; Molecular Docking Simulation ; Cell Movement/drug effects ; Receptors, Purinergic P2Y2/metabolism ; Signal Transduction/drug effects ; Calcium/metabolism ; Cell Line ; Cell Survival/drug effects ; Structure-Activity Relationship

Recent data indicate that extracellular ATP affects wound healing efficacy via P2Y2-dependent signaling pathway. In the current work, we propose double-modified ATP analogue-alpha-thio-beta,gamma-methylene-ATP as a potential therapeutic agent for a skin regeneration. For the better understanding of structure-activity relationship, beside tested ATP analogues, the appropriate single-modified derivatives of target compound, such as alpha-thio-ATP and beta,gamma-methylene-ATP, were also tested in the context of their involvement in the activation of ATP-dependent purinergic signaling pathway via the P2Y2 receptor. The diastereomerically pure alpha-thio-modified-ATP derivatives were obtained using the oxathiaphospholane method as separate S P and R P diastereomers. Both the single- and double- modified ATP analogues were then tested for their impact on the viability and migration of human keratinocytes. The involvement of P2Y2-dependent purinergic signaling was analyzed in silico by molecular docking of the tested compounds to the P2Y2 receptor and experimentally by studying intracellular calcium mobilization in the human keratinocytes HaCaT. The effects obtained for ATP analogues were compared with the results for ATP as a natural P2Y2 agonist. To confirm the contribution of the P2Y2 receptor to the observed effects, the tests were also performed in the presence of the selective P2Y2 antagonist-AR-C118925XX. The ability of the alpha-thio-beta,gamma-methylene-ATP to influence cell migration was analyzed in vitro on the model HaCaT and MDA-MB-231 cells by wound healing assay and transwell migration test as well as in vivo using zebrafish system. The impact on tissue regeneration was estimated based on the regrowth rate of cut zebrafish tails. The in vitro and in vivo studies have shown that the S P -alpha-thio-beta,gamma-methylene-ATP analogue promotes regeneration-related processes, making it a suitable agent for enhance wound healing. Performed studies indicated its impact on the cell migration, induction of epithelial-mesenchymal transition and intracellular calcium mobilization. The enhanced regeneration of cut zebrafish tails confirmed the pro-regenerative activity of this ATP analogue. Based on the performed studies, the S P -alpha-thio-beta,gamma-methylene-ATP is proposed as a potential therapeutic agent for wound healing and skin regeneration treatment.
(© 2024. The Author(s).)

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2017/26/D/ST5/01046 National Science Centre in Poland; 2023/49/B/ST4/03288 National Science Centre in Poland

Keywords: ATP analogue; P2Y2 receptor; Purinergic signaling; Skin regeneration; Wound healing

8L70Q75FXE (Adenosine Triphosphate)
0 (Receptors, Purinergic P2Y2)
SY7Q814VUP (Calcium)

Date Created: 20240607 Date Completed: 20240607 Latest Revision: 20240610

20240611

PMC11161507

10.1038/s41598-024-63759-5

38849425