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

Abstract

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.

TRF1 and TRF2: pioneering targets in telomere-based cancer therapy

“…Further work is required to elucidate the specific residues critical for TIN2 interaction (Lim et al 2017 ). Additionally, the disruption of the shelterin complex by specific molecules may lead to the blocking of TRF1-TIN2 interaction, resulting in cellular senescence (Brankiewicz et al 2023 ) Fig. 2 .…”

“…This complex, consisting of six core proteins (TRF1, TRF2, RAP1, TIN2, TPP1, and POT1), plays a crucial role in protecting telomeres and maintaining genomic stability. Targeting these proteins offers a novel approach to cancer treatment, but it also presents unique challenges, including drug resistance, off-target effects, and delivery issues (Brankiewicz et al 2023 ). The rationale behind targeting the shelterin complex in cancer therapy stems from its central role in telomere protection and the regulation of telomerase activity.…”