Transcription factors and other intracellular protein-protein interactions remain challenging therapeutic targets. This presentation describes an integrated live-cell discovery platform combining genetically encoded peptide libraries, intracellular cyclisation, functional selection and scalable hit validation. By constraining peptides during selection, the workflow enriches cell-tolerated, biostable antagonists that disrupt transcription factor-DNA and protein-protein interactions. The approach links library design, screening, sequencing-based prioritization, biophysical characterization and cellular validation to accelerate discovery of functional, cell-active constrained peptides.

Intrinsically disordered regions regulate signaling and often drive disease, yet their flexibility and lack of stable pockets make them difficult to target. We developed deep-learning based computational approaches to design de novo proteins that recognize flexible sequences, post-translationally modified epitopes, and aggregation-prone regions. These binders showed specificity and enabled applications in oncology, immunology, virology, and neurodegeneration, including CAR-T targeting, MYC inhibition, HBx suppression, and Tau degradation. We also designed sequence-specific metalloproteases that cleave disease-relevant regions of TDP-43. Together, this work establishes a platform for converting dynamic molecular states into selective, therapeutically actionable targets across the proteome.

By integrating approximately 200,000 mass spectrometry datasets with ribosome profiling and immunopeptidomics resources, we identified more than 4,000 translated products from 7,264 non-canonical open reading frames (ncORFs), termed peptideins. Functional validation and evolutionary analyses demonstrate their roles in cell essentiality and medulloblastoma survival, revealing a previously hidden class of biologically relevant peptides that expands the human proteome and offers new opportunities for peptide discovery and therapeutic development.

Protein–protein interactions (PPIs) remain challenging therapeutic targets, particularly within cells where biologics cannot reach. We developed SnipeTide technology, a platform generating orally available, cell-permeable macrocyclic peptides that combine antibody-like target binding with intracellular accessibility. By integrating drug-likeness criteria and proprietary peptide library technologies, SnipeTide enables the discovery of drugs against previously undruggable intracellular PPIs.

The development of targeted therapeutics requires balancing the exceptional specificity of antibodies with the manufacturability, tissue penetration, and chemical versatility of peptides. We have developed a peptide engineering platform that converts phenotypic screen-selected domain antibodies into structurally constrained cyclic peptides that preserve antibody-derived binding while enabling modular therapeutic conjugation. This presentation will describe our integrated discovery workflow, including phenotypic phage display, computational CDR3 analysis, cyclic peptide engineering, and functional validation. We will discuss how this platform enables the scalable development of compact, high-affinity targeting ligands for precision drug delivery and next-generation therapeutic applications.