Now many years ago, I was in a chemical biology lab (= interrogating/modifying "biology" with "chemical" tools, half organic synth half pharma/bio) around the time that the term "click chemistry" became popular, and the PI got really fired up about it. Lots of other lab groups in adjacent departments were also really fired up about it.

Side note, "click chemistry" is kind of a marketing term in that it describes a process for modular assembly of moieties in one step in "biocompatible" conditions i.e. water without much poison in it, but which doesn't actually describe how to do that.

The first realization of this vision (or at least the first previously discovered system described as click chem) was copper catalyzed azide-alkyne cycloaddition, and for quite a while this was the only "click" reaction.

Omitting for brevity all the things that were attempted and reasons for doing so as they've been elaborated elsewhere in sibling threads, it was basically impossible to get anything working on/in actual living cells (or "embalmed" cells) although the "click" reaction worked fine in isolation. The parameter space here is pretty big; pharmacology of the things, copper concentration, temperature, time, doing all kinds of things to the cells, and we never figured it out, so it's tricky to find a root cause. One failure mode seemed to be that the copper catalyst caused protein aggregation and the labels being added stuck to the aggregates better than they stuck to the "click handle" alkyne, and there were other failure modes more related to pure pharmacology that probably also contributed (e.g. when the drug sticks to the target it does so in a position that blocks the alkyne "click handle" from being accessible). It was also impossible to reproduce a lot of high profile click labeling papers.

That point now seems like the trough of the hype cycle, so to speak. Apparently Bertozzi's subsequent work with strain promoted cycloadditions (= no protein-aggregating copper) is much more useful.

I'm guessing other people with negative commentary got burned by the early promises of click chem in the real world -- Also, that Sharpless got it for an abstract "product vision" (the award is because "he coined the concept of click chemistry, which is a form of simple and reliable chemistry"), Meldal got it for the CuAAC reaction which actually sucks for biology, and Bertozzi's work doesn't stand on its own.

It seems “simple” from a chemistry perspective. But as pointed out, the special part is that this is simple chemistry, _that also works in standard biological conditions_ without harming biology: bio-orthogonal. So it allows complex chemistries to be brought into biological contexts easily and completely. So the discoveries made with this novel chemistry will be biological in nature. That makes for an awkward audience when one is siloed either on the chemistry side or the biology side and can’t quite see how much of a door is opened when you combine the disciplines.