Biospecific Chemistry for Covalent Linking of Biomacromolecules
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Lei Wang, Ph.D.
Professor, Department of Pharmaceutical Chemistry
University of California, San Francisco
Lei Wang received BS and MS from Peking University mentored by Zhongfan Liu, and PhD from UC Berkeley mentored by Peter G. Schultz. His graduate research resulted in the first expansion of the genetic code to include unnatural amino acids (Uaas) in 2001, for which he was awarded the Young Scientist Award by the journal Science. After postdoctoral training with Roger Y. Tsien, Wang started his group at the Salk Institute in 2005, and moved to UCSF in 2014. Wang’s group has developed new methods for the expansion of the genetic code in a variety of cells and model organisms, including mammalian cells, stem cells, C. elegans, and recently embryonic mouse. His group discovered that release factor one (RF1) is nonessential in E. coli, and engineered autonomous bacteria capable of incorporating Uaas at multiple sites with high efficiency. By developing the concept of proximity-enabled bioreactivity, Wang’s group designed and demonstrated that a new class of Uaas, the bioreactive Uaas, can be genetically encoded in live systems. These bioreactive Uaas enable novel covalent bonding abilities to be specifically introduced into proteins and biosystems, opening the door for new protein engineering and biological research in vivo. Wang is a 2006 Beckman Young Investigator, a 2006 Searle Scholar, a 2008 National Institutes of Health Director’s New Innovator Award recipient, and the 2021 Emil Thomas Kaiser Award recipient of the Protein Society.
Summary
Noncovalent interactions among biomacromolecules are fundamental to biological processes. However, recent advances in biospecific chemistry have enabled the formation of covalent bonds between biomacromolecules both in vitro and in vivo. This has been accomplished by genetically encoding latent bioreactive amino acids into proteins. These amino acids selectively react with nearby natural groups through proximity-enabled bioreactivity, allowing for covalent targeting of biomacromolecules without altering the target. By expanding the genetic code, various latent bioreactive amino acids have been designed and incorporated into proteins, enabling the specific targeting of protein residues, RNA, and carbohydrates. The resulting covalent linkages can promote challenging protein properties and capture transient protein−protein and protein−RNA interactions in vivo. Furthermore, proximity-enabled reactive therapeutics (PERx) has been developed to create covalent protein therapeutics, with applications in cancer immunotherapy, viral neutralization, and targeted radionuclide therapy.
Presentation Objectives:
- Understand the core principles of biospecific chemistry, which allows for covalent and specific targeting of biomacromolecules without altering the target.
- Explore how biospecific chemistry and covalent targeting open new pathways for advancing basic biological research.
- Recognize the potential of biospecific chemistry in developing the next-generation of covalent biologics.
https://videocast.nih.gov/watch=55004
This page was last updated on Monday, September 16, 2024