# In Silico–Designed TGFβRI/TGFβRII Receptor Complex Peptide Inhibitors Exhibit Biological Activity In Vitro

## TL;DR

Scientists designed peptides to block TGFβ signaling, which is involved in various diseases, and found they work well without harming cells.

## Contribution

Novel in silico-designed peptide inhibitors of the TGFβ/TGFβRI/TGFβRII complex with biological activity and no cytotoxicity.

## Key findings

- Peptide inhibitors significantly reduced luminescence in HEK293T cells, indicating TGFβ pathway inhibition.
- Three peptides showed effects comparable to the known inhibitor SD-208 without causing cell toxicity.
- PIs may be useful for treating fibrotic disorders, chronic inflammation, or certain cancers.

## Abstract

TGF‐β (transforming growth factor β) is a pleiotropic cytokine found in three isoforms in humans. It regulates cell proliferation, wound healing, immune cell recruitment, contributes to epithelial‐to‐mesenchymal transition (EMT) and to the conversion of fibroblasts to myofibroblasts. TGF‐β signalling pathway hyperactivity underlies many human disorders. The aim of this study was to evaluate a series of novel, in silico–designed peptide inhibitors (PIs) of the TGFβ/TGFβRI/TGFβRII complex. Luciferase‐based luminescence assays on HEK293T cells were used to comparatively assess PI biological activity and calculate IC50 values. Flow cytometry was used to assess PI cytotoxicity on HEK293T cells. The PIs caused significant luminescence level reductions compared to controls. Additionally, three of the PIs caused luminescence reductions that did not differ significantly from the effects of SD‐208, a small molecule TGFβ inhibitor. None of the PIs exhibited cytotoxicity. Our TGFBR PIs have demonstrated activity in vitro, with no observed cytotoxicity. Our results suggest the PIs may be of interest in the treatment of fibrotic disorders, chronic inflammatory diseases, or certain neoplastic cancers. The PIs will be further refined in silico and tested via assays carried out on cancer cell lines and CD4+/CD8+ T cells.