Tailoring Azirine Reactivity for Biological Applications

Researchers from Boston College are developing novel bioconjugation reactions that selectively engage native functional groups in proteins. Such reactions are highly sought after in proteomics, protein engineering, and the development of protein therapeutics. Their importance has also been recognized in the field of covalent drug discovery, where reactive groups are used to achieve selective and durable protein inhibition. However, the development of covalent drugs has been limited by the scarcity of suitable reactive groups chemistries. To address this challenge, the Boston College research team will systematically investigate emerging chemotypes that have shown promise for the modification of native proteins. In particular, the team will explore how the reactivity and selectivity of these chemotypes can be tuned to enable programmable engagement with a diverse range of protein functional groups. Successful completion of this project will deliver a collection of novel chemotypes for streamlined covalent drug design, as well as versatile protein modification towards various applications in biotechnology. Importantly, this interdisciplinary effort will provide a robust training platform for the next generation of scientists, including graduate students, undergraduate researchers, and high school interns. Bioconjugation reactions are foundational tools across many areas of protein science, ranging from in vivo protein imaging to the development of covalent therapeutics. While numerous bioorthogonal conjugation strategies have been successfully implemented in engineered proteins, the selective modification of specific side chains in native proteins remains a significant challenge. This challenge is particularly acute in covalent drug discovery, where precisely tuned reactivity profiles are essential for effective warhead design. With support from this grant, researchers at Boston College will investigate and develop novel chemotypes capable of predictable and selective conjugation with a variety of protein nucleophiles. Specifically, the team will examine the reactivity, selectivity, and structure–activity relationships of azirines, an emerging class of reagents for native protein modification. This work is expected to yield new methodologies for site-selective protein modification without the need for incorporation of noncanonical amino acids. In addition, it will provide fundamental insights into the structure–reactivity relationships of azirines, guiding their future application as covalent warheads in drug discovery. Through its multidisciplinary nature, the project will also provide valuable research and training opportunities for graduate students, undergraduates, and high school interns, preparing them to address future challenges in the chemical sciences. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.