The drive to better understand living systemsand the pursuit of more effective clinical toolshave fueled a surge in research at the intersec-tion of chemistry, biology, and medicine. A com-mon motif in this work has been the modifica-tion of biologically active molecules to createprobes for the interrogation of biologic systemsand to produce diagnostics and therapeutics forthe clinic. Yet the chemical manipulation of bio-molecules — whether small molecules, nucleicacids, carbohydrates, lipids, proteins, or anti-bodies — is complicated by three challenges.First, nature uses only a handful of functionalgroups (e.g., amines and carboxylic acids), eachwith its own demands when it comes to reactivity.Second, a biomolecule can often contain multi-ple copies of a given functional group, and tomake matters worse, some of these can be situ-ated in the area responsible for its biologic activ-ity. As a result, modifying a biomolecule at asingle site without perturbing its function canbe a daunting task. Third, many biomoleculesare highly sensitive to temperature, solvent, andpH and can therefore be manipulated only underbiocompatible conditions. Historically, these in-trinsic obstacles have combined to make thesynthesis of effective biomolecular tools arduousat best and impossible at worst.
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