Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233, Gdansk, Poland.
International Centre for Cancer Vaccine Science, University of Gdansk, ul. Kładki 24, 80-822, Gdańsk, Poland.
Chemistry. 2023 Oct 2;29(55):e202300970. doi: 10.1002/chem.202300970. Epub 2023 Sep 4.
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.
在这项工作中，我们研究了相对较新且尚未充分探索的潜在抗癌靶点——庇护蛋白，特别是端粒结合因子 1（TRF1）蛋白可被计算机设计的“肽拟似物”分子所阻断。TRF1 可直接与 TIN2 蛋白相互作用，而这种蛋白-蛋白相互作用对于端粒的正常功能至关重要，我们的新型修饰肽分子可阻断这一相互作用。我们的化疗方法基于以下假设：调节 TRF1-TIN2 相互作用可能对癌细胞更具危害性，因为癌细胞的端粒比正常细胞更脆弱。我们通过 SPR 实验证明，我们的修饰肽 PEP1 分子与 TRF1 相互作用，可能占据 TIN2 蛋白的原始结合位点。研究中使用的分子对庇护复合物的干扰在短期内可能不会导致细胞毒性，但阻断 TRF1-TIN2 会导致所使用的乳腺癌细胞系发生细胞衰老，这可作为癌症模型。因此，我们的化合物似乎可用作精确阻断 TRF 蛋白的起始模型化合物。
