Research Projects

The selective binding of TRAIL to death receptors (DRs) in cancer cells has been explored as a potential therapy. However, current therapies have faced challenges such as resistance, toxicity, and incomplete tumor eradication. To overcome these issues, researchers propose using novel peptide ligands that mimic TRAIL and efficiently trimerize DR5 through a smart supramolecular assembly of multivalent ligands. The binding interface of the TRAIL-DR5 complex has been studied, and a quick in silico study revealed that multi helix bundles or multivalent beta-sheet ligands can tightly regulate the DR5 clustering process through selective interaction. A super-secondary scaffold-based approach will be selected for virtual screening (VS) to understand interaction modules and favorable binding modes. Promising hit sequences from VS will be synthesized and validated through fluorescence polarization assay with DR5. A potent binder to DR5 will be targeted library preparation via'split-mix' technology using unnatural amino acid variables at hot spot residues. The cleaved peptides will be subjected to screen in solution and ligand enrichment to target. The enriched ligands bound to DR5 will be separated by size-exclusion chromatography and sequenced via MS-MS. High-affinity ELs will be subjected to rigorous IC50 measurement on two different cancer cell lines (A549 and MCF7) using FACS and MTT assay. The lead peptide sequences will be conjugated in a cyclic peptide frame via the diazaborine biorthogonal reaction to prepare a trivalent/polyvalent ligand. A covalent probe will be installed to boost affinity by capturing Lys45 in the DR5 binding site. The multivalent ligand potency will be evaluated by testing with numerous cancer cells and tissues of various cancer patients, ultimately impacting the opening for cancer treatment.