Generation of functional oligopeptides that promote osteogenesis based on unsupervised deep learning of protein IDRs

Deep learning(DL)is currently revolutionizing peptide drug development due to both computational advances and the substantial recent expansion of digitized biological data.However,progress in oligopeptide drug development has been limited,likely due to the lack of suitable datasets and difficulty in identifying informative features to use as inputs for DL models.Here,we utilized an unsupervised deep learning model to learn a semantic pattern based on the intrinsically disordered regions of～171 known osteogenic proteins.Subsequently,oligopeptides were generated from this semantic pattern based on Monte Carlo simulation,followed by in vivo functional characterization.A five amino acid oligopeptide(AIB5P)had strong bone-formation-promoting effects,as determined in multiple mouse models(e.g.,osteoporosis,fracture,and osseointegration of implants).Mechanistically,we showed that AIB5P promotes osteogenesis by binding to the integrin a5 subunit and thereby activating FAK signaling.In summary,we successfully established an oligopeptide discovery strategy based on a DL model and demonstrated its utility from cytological screening to animal experimental verification.