Water is the solvent of life. Nature’s proficiency at synthesizing complex molecules in aqueous environments is unparalleled. Enzymes have evolved to perform chemical reactions in water with exquisite efficiency and selectivity. Alternatively, the advancement of chemical synthesis has primarily occurred in organic solvents. While recent efforts have focused on developing environmentally sustainable reactions in water, many transformations are still unsuitable for aqueous conditions due to issues of (1) solubility and (2) side reactions with water. In particular, these synthetic methods are often incompatible with biomolecular substrates, such as peptides and proteins, which require aqueous solvent.
Peptides and proteins are versatile compounds with a growing list of therapeutic applications to treat various ailments, including cancer, diabetes, and infections. Normally derived from the 20 natural amino acids (AAs), these biomolecules can be easily synthesized and folded into a myriad of unique structures. Their modularity enables the rapid screening of large libraries to discover medicinally relevant sequences. The development of peptide and protein-based medicines, however, often requires that chemical modifications be made to their natural sequences in order to enhance their stability or activity. Performing reactions on biomolecules is challenging given their structural complexity and the need for aqueous solvent. Research in our group is focused on the development of aqueous transformations that are both environmentally friendly and compatible with peptide and protein substrates. In particular, we are designing (1) bioconjugation techniques that are capable of covalently modifying peptides and proteins with chemical reactions, and (2) cleavable linkers that enable the release of essential cargo from biomolecules.