We are exploring the discovery of new chemical reactions and synthetic strategies to develop a comprehensive, robust, and cost-effective methodology that would overcome the limits of biology to enable de novo chemical synthesis of any naturally evolved or artificially designed protein. To realize this aspiration, we need, and are therefore developing, new chemistries to achieve three specific objectives: 1) easy-to-use peptide ligation chemistries for rapid and efficient synthesis of protein structural domains, 2) robust temporary structural support strategies for the ligation and folding of challenging targets, and 3) efficient transpeptidative protein domain-domain assembly reactions for multidomain proteins. Starting from the fundamental idea of chemistry that all molecules can be created from atoms in a bottom-up fashion, the ability to synthesize proteins of any conceivable structure will pave an important path for exploring nature and developing products.

1) Exploring nature. Dynamic protein-protein interactions (PPIs) regulated by protein post-translational modifications (PTMs) play key roles in basic biology and disease. These PPIs are often weak and transient, and their comprehensive identification and rigorous characterization are indispensable yet challenging tasks in modern biomedicine. We are developing chemistry to synthesize structurally well-defined proteins that can carry any PTMs, and using them to develop technologies (e.g., synthetic protein tools and antibodies) for proteomic mapping, biochemical reconstitution, structural elucidation, functional annotation, and drug intervention studies, which will enable deeper elucidation of the dynamic PPI networks through a higher-resolution lens. Research efforts in this direction will help explore how chemical protein synthesis can contribute to the drug development studies to confront the next stage of biomedical challenges.

2) Developing products. Chemically synthesized proteins, which may contain any custom-designed unnatural structural units beyond biological constraints, offer new and unique opportunities for the development of high value-added products. Artificial intelligence (AI)-assisted generative molecular design can overcome the difficulty of screening ultra-large molecular libraries and is particularly suited to facilitate the studies on unnatural synthetic proteins. We are investigating how AI-assisted generative molecular design can be combined with chemical protein synthesis to develop functional molecules (e.g., molecular glues, cyclic peptides, antibodies, and enzymes) by using and accumulating better collection of high-quality decision-making information and experimental data. Research efforts in this direction will help explore how chemical protein synthesis can contribute to the discovery and development of a new generation of useful molecules.