Cosomil! Single Molecule Enzyme Activity

Recently I came across Cosomil¹.

I find the approach quite interesting… essentially most of the enzyme detection methods we use are somewhat indirect they use labelled antibodies to detect the presence of proteins.

Of course there are bulk measurements through which we infer enzyme activity, and that are commonly used in diagnostics².

But the idea that we’d test enzymes for their activity directly, using a special substrate which we can measure seems a little novel. And the idea that we can do that on a single molecule level even more so.

That appears to be what Cosomil are developing.

A 2020 paper describes the approach. Here they focused on alkaline phosphatase (ALP). Here they designed novel substrates which contained a fluorphore which could be detected in the reaction product³.

You can then use this in a single molecule context by loading the enzymes into wells (4 micron). I assume because you are generating a ton of product, the imaging system seems quite simple (20x dry objective).

The result is a digital readout⁴, with the whole thing being a little reminiscent of the Quanterix platform.

What’s neat, is this isn’t just a on/off signal because you also get a measurement of the degree of activity:

Cosomil appear to be pitching this squarely at liquid biopsy. While perhaps not impossible, this seems like a challenging market to go after.

Other diagnostic or commercial applications perhaps might be a better short term fit?

There are clearly issues, like the need to design a new substrate for every enzyme… but it feels like there should be a market out there?

Will be interesting to see where they take this!

1. I live in Japan. And I’m often ask about interesting Japanese startups.

My answer is generally that I’m unaware of any.

Japanese life science startups have several problems one of which is that they are often led by non-technical, non-scientific CEOs (seemingly not the case with Cosomil!) and that causes numerous problems.

Another issue is that globally life science (and other) startups are fairly localized to a couple of places in the US, with a few in the UK and Europe.

But I decided to see if I could find any, which is how I came across Cosomil. If you come across any others, let me know!

2. Testings for Urease by looking at released CO2 etc. is the kind of thing I’m thinking of.

3. “Specifically, the excited state of the fluorophore in the intact (protected) probe was designed to accept a single electron from the 8-aryl group of xanthene so that the fluorophore can revert back to its ground state without emitting fluorescence, whereas this did not occur in the reaction product (deprotected phenolate fluorophore). We optimized the scaffold by tuning the electron density of the 8-aryl group of TG (fig. S3 and discussion S2) and synthesized a 2,4-dimethoxybenzenesulfonic acid derivative, which was expected to exhibit marked increase in fluorescence upon hydrolysis of the protected form to the phenolate while showing sufficient hydrophilicity due to the presence of a sulfonic acid moiety”

4. More plots from the real samples in the paper…