WALS: Biospecific Chemistry for Covalent Linking of Biomacromolecules

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. LECTURE 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.
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