Location-agnostic site-specific protein bioconjugation via Baylis Hillman adducts

Mudassir H. Mir, Sangeeta Parmar, Chhaya Singh and Dimpy Kalia ()
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Mudassir H. Mir: Indian Institute of Science Education and Research (IISER) Bhopal
Sangeeta Parmar: Indian Institute of Science Education and Research (IISER) Bhopal
Chhaya Singh: Indian Institute of Science Education and Research (IISER) Bhopal
Dimpy Kalia: Indian Institute of Science Education and Research (IISER) Bhopal

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Proteins labelled site-specifically with small molecules are valuable assets for chemical biology and drug development. The unique reactivity profile of the 1,2-aminothiol moiety of N-terminal cysteines (N-Cys) of proteins renders it highly attractive for regioselective protein labelling. Herein, we report an ultrafast Z-selective reaction between isatin-derived Baylis Hillman adducts and 1,2-aminothiols to form a bis-heterocyclic scaffold, and employ it for stable protein bioconjugation under both in vitro and live-cell conditions. We refer to our protein bioconjugation technology as Baylis Hillman orchestrated protein aminothiol labelling (BHoPAL). Furthermore, we report a lipoic acid ligase-based technology for introducing the 1,2-aminothiol moiety at any desired site within proteins, rendering BHoPAL location-agnostic (not limited to N-Cys). By using this approach in tandem with BHoPAL, we generate dually labelled protein bioconjugates appended with different labels at two distinct specific sites on a single protein molecule. Taken together, the protein bioconjugation toolkit that we disclose herein will contribute towards the generation of both mono and multi-labelled protein-small molecule bioconjugates for applications as diverse as biophysical assays, cellular imaging, and the production of therapeutic protein–drug conjugates. In addition to protein bioconjugation, the bis-heterocyclic scaffold we report herein will find applications in synthetic and medicinal chemistry.

Date: 2024
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DOI: 10.1038/s41467-024-45124-2

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