Contemporary approaches to site-selective protein modification

Proteins constitute the majority of nature’s worker biomolecules. Designed for specific functions, complex tertiary structures make proteins ideal candidates for analyzing natural systems and creating novel biological tools. Due to both large size and the need for proper folding, de novo synthesis of proteins has been quite a challenge, leading scientists to focus on modifying protein templates already provided by nature. Recently developed methods for protein modification fall into two broad categories: those that can modify the natural protein template directly and those that require genetic manipulation of the amino acid sequence prior to modification. The goal of this review is to provide not only a window through which to view the many opportunities created by novel protein modification techniques, but also to act as an initial guide to help scientists find direction and form ideas in an ever-growing field. In addition to the highlighting methods reported in the past five years, we aim to provide a broader sense of the goals and outcomes of protein modification and bioconjugation in general. While the main body of the paper comprises reactions directly involving proteins as a starting material, some further functionalization strategies as well as biological applications are also acknowledged. The discussion concludes by speculating what trends and discoveries will most likely come next in the field