Development of alternative linear peptides for targeting αvβ3 integrin has attracted much attention, as the traditional peptide ligand, cyclic RGD, is limited by inferior water-solubility and complex synthesis. Using pharmacophore-based virtual screening and high-throughput molecular docking, we identified two novel linear small peptides RWr and RWrNM with high affinity and specificity to αvβ3 integrin. The competitive binding with cyclic RGD (c(RGDyK)) and cellular uptake related to the integrin expression levels verified their affinity to αvβ3 integrin. The intermolecular interaction measurement and dynamics simulation demonstrated the high binding affinity and stability, especially for RWrNM. In vivo peptide-guided tumor imaging and targeted therapy further confirmed their specificity. Results indicated that the newly identified small linear peptide RWrNM, with high affinity and specificity to αvβ3 integrin, better water-solubility, and simplified synthetic process, could overcome limitations of the current cyclic RGD peptides, paving the way for diverse use in diagnosis and therapy.
Keywords: binding affinity.; linear peptide; αvβ3 integrin.