Modified Peptide Molecules As Potential Modulators of Shelterin Protein Functions; TRF1

In this work, we present studies on relatively new and still not well‐explored potential anticancer targets which are shelterin proteins, in particular the TRF1 protein can be blocked by in silico designed “peptidomimetic” molecules. TRF1 interacts directly with the TIN2 protein, and this protein‐pr...

Full description

Saved in:
Bibliographic Details
Published in:Chemistry : a European journal 2023-10, Vol.29 (55), p.e202300970-n/a
Main Authors: Brankiewicz, Wioletta, Kalathiya, Umesh, Padariya, Monikaben, Węgrzyn, Katarzyna, Prusinowski, Maciej, Zebrowska, Joanna, Zylicz‐Stachula, Agnieszka, Skowron, Piotr, Drab, Marek, Szajewski, Mariusz, Ciesielski, Maciej, Gawrońska, Małgorzata, Kallingal, Anoop, Makowski, Mariusz, Bagiński, Maciej
Format: Article
Language:English
Subjects:
Cancer
Chemistry
Cytotoxicity
modified peptides
Modulators
Peptides
Proteins
Senescence
shelterin proteins
Telomeres
TRF1 modulation
TRF1 protein
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In this work, we present studies on relatively new and still not well‐explored potential anticancer targets which are shelterin proteins, in particular the TRF1 protein can be blocked by in silico designed “peptidomimetic” molecules. TRF1 interacts directly with the TIN2 protein, and this protein‐protein interaction is crucial for the proper functioning of telomere, which could be blocked by our novel modified peptide molecules. Our chemotherapeutic approach is based on assumption that modulation of TRF1‐TIN2 interaction may be more harmful for cancer cells as cancer telomeres are more fragile than in normal cells. We have shown in vitro within SPR experiments that our modified peptide PEP1 molecule interacts with TRF1, presumably at the site originally occupied by the TIN2 protein. Disturbance of the shelterin complex by studied molecule may not in short term lead to cytotoxic effects, however blocking TRF1‐TIN2 resulted in cellular senescence in cellular breast cancer lines used as a cancer model. Thus, our compounds appeared useful as starting model compounds for precise blockage of TRF proteins. In silico designed N‐modified tripeptide PEP1 (yellow) imitating TIN2 peptide (green) can modulate interaction of TIN2 with TRF1 telomeric shelterin protein (gray) as shown in the figure and in consequence cause biological effects in cancer cells leading to senescence.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.202300970