Mapping targetable sites on the human surfaceome for the design of novel binders

Abstract The human cell surfaceome, integral to cell communication and disease mechanisms, presents a prime target for therapeutic intervention. De novo protein binder design against these cell surface proteins offers a promising yet underexplored strategy for drug development. However, the vast search space and limited data on natural or competitive binders have historically limited experimental success. In this study, we systematically analyzed the entire human surfaceome, identifying approximately 4,500 targetable sites and introducing high-quality binder seeds tailored for protein design applications. To validate these seeds, we implemented two experimental approaches (protein scaffolding and peptide cyclization) on three representative targets (FGFR2, IFNAR2, and HER3). Our results revealed a high success rate, emphasizing the precision and therapeutic potential of these seeds, as well as the need for constant improvements of computational protein design pipelines utilizing machine learning and physics-based methods. Additionally, we present SURFACE-Bind, an interactive database offering open access to all generated data. The high-throughput computational design methods and target-specific binder seeds established here pave the way for a new generation of targeted therapeutics for the human surfaceome.