We are developing a comprehensive methodology for de novo chemical protein synthesis, thereby enabling the creation of functional proteins that transcend biological constraints. Its core comprises: 1) Self-adaptive solid-phase chemistries for ultrafast production of complex peptides; 2) Peptide hydrazide ligation for efficient synthesis of protein domains; 3) Catalytic transpeptidative reactions for hierarchical assembly of multi-domain proteins. Using this methodology, we design and synthesize an expanding repertoire of proteins across an unbounded chemical space to advance biomedical research and product development. Key applications include: 1) Proteins with complex post-translational modifications (PTMs)—used to elucidate the dysregulation of PTM-associated protein-protein interactions in diseases and their rewiring by therapeutics (e.g., molecular glues); 2) Pragmatic unnatural proteins (e.g., cyclic peptides, artificial enzymes) derived via AI-driven generative molecular design—which are functionally more versatile and potent than biologically produced proteins.