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Development of bioorthogonal chemical reporters for studying host-pathogen interactions

  • Author(s): Nazarova, Lidia
  • Advisor(s): Prescher, Jennifer A
  • et al.
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Abstract

Bioorthogonal chemical reporters are small functional groups that can be metabolically incorporated into biomolecules by the cell’s native metabolic machinery. These moieties can be covalently modified with probes for detection or isolation. I applied this strategy to profile glycoproteins in Toxoplasma gondii, a prevalent intracellular parasite that infects nearly one-third of the world's population and may cause life-threatening conditions in immunocompromised patients. Using the bioorthogonal chemical reporter strategy, I identified a large, diverse set of glycosylated proteins in T. gondii including some previously unannotated proteins likely involved in modulating host-parasite interactions.

In addition to glycosylated structures, parasites and host cells exchange numerous other metabolites. Simultaneous monitoring of these communication pathways requires multiple cell-compatible reactions that can be used concurrently, or “mutually orthogonal” bioorthogonal chemistries. Unfortunately, the existing toolbox of bioorthogonal chemistries is rather sparse, limiting our ability to look at multiple biomolecules in tandem. As part of Prescher lab, I have contributed to the development of novel chemical reporters for simultaneous profiling of host-pathogen crosstalk. My labmates and I established a new bioorthogonal chemical reaction—a cycloaddition between 1,3-disubstituted cyclopropenes and tetrazines—that can be used in living systems. Excitingly, this reaction can be used in tandem with common azide-alkyne chemistries for multi-component imaging. We also demonstrated that 1,3-disubstituted cyclopropenes can be used concurrently with isomeric cyclopropenes—3,3- cyclopropenes—in biological labeling applications. Both of these molecules harbor unique reaction preferences, enabling them to be used simultaneously. This was noteworthy result, since the structures of these cyclopropenes only differ by the placement of a single methyl group. I also developed another orthogonal chemical reporter for use in multi-component applications: methylene cyclopropane. This molecule exhibits unique cycoaddition reactivities and is poised to join the ranks of useful chemical reporters.

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This item is under embargo until June 3, 2021.