Biochemistry and biomedical chemistry
Bioorthogonal reactions
Bioorthogonal chemistry uses selective reactions that proceed in biological settings without materially perturbing native biochemistry.
IntuitionIntuition: the central idea
Bioorthogonal chemistry uses selective reactions that proceed in biological settings without materially perturbing native biochemistry.
SchoolSchool level: key concepts and a first application
Definition: Core concept
A biomolecule is first equipped with a non-native handle; a complementary probe then forms a covalent conjugate. Strain-promoted azide–alkyne cycloaddition and tetrazine ligation are common families.
Azides and strained alkynes are compact handles. The reaction must run selectively in water, at physiological temperature and concentration, without attacking natural functional groups.
| Term | Interpretation |
|---|---|
| Azide | A small non-native handle stable in many biological settings. |
| Strained alkyne | Ring-strained alkyne that reacts rapidly with azides without copper. |
| Tetrazine ligation | Very fast inverse-electron-demand cycloaddition, often with trans-cyclooctene. |
Example: Apply the idea
Why can a reaction that is highly selective in buffer fail in a living-cell labeling experiment?
Solution
The handle may be unstable or inaccessible, the probe may not enter cells, and competing biomolecules or toxicity can limit useful conversion.
UndergraduateUniversity level: quantitative description
Reaction choice balances rate, reactant stability, selectivity and ease of incorporation into biomolecules; no single chemistry is optimal everywhere.
AdvancedAdvanced: assumptions and mechanistic detail
At the frontier, reaction choice is coupled to genetic encoding, delivery, photostability and intracellular environment. Fast tetrazine chemistry and strain-promoted cycloaddition remain complementary.
ResearchResearch frontier: open questions and current practice
References
- Cell surface engineering by a modified Staudinger reaction · Eliana Saxon; Carolyn R. Bertozzi, 2000
- A strain-promoted [3 + 2] azide–alkyne cycloaddition for covalent modification of biomolecules in living systems · Nicholas J. Agard; Jennifer A. Prescher; Carolyn R. Bertozzi, 2004