What is the name of the methodology?
Rapid discovery of high affinity binders for proteins of interest from ultra large chemical libraries

Oncode Investigator name
Sebastian Pomplun

What is the methodology good for?
Our platform can rapidly identify novel (or optimized) binders for protein targets of interest. We can screen diverse chemical space, including peptides, macrocycles and small molecules. The platform screens libraries of 10k-10million compounds, all at once, in affinity selections against a given target protein. Hits are pulled out and identified via tandem mass spectrometry followed by decoding with automated structure annotation software. 

What is/are the main advantages of this methodology over related technologies (1-3 sentences)?
Compared to classical high throughput screenings our platform is much more affordable, rapid and user friendly. Compared to phage display (and related tech) we are not limited to natural peptides and can explore much larger and more druglike chemical space. If initial ligands for the target are known, often it is quite simple building a focused library for rapid binder optimization

What are the most important limitations of the methodology (1-3 sentences)?
The technology is still young and under development. We do not identify ligands for any target we try. Likely we are limited to identifying high affinity binders (<100 nM).
The technology, for now, works only with purified, soluble proteins.
The platform identifies ‘binders’ and not per se ‘active’ compounds.

What type of samples are compatible with methodology (yes, no, possibly)

What future developments to the methodology are you planning, if any?
We aim to optimize the selection protocols in order to achieve higher hit rates for any given target. Toward this goal we will work on different library designs and sizes, the workflow itself, and the hit decoding software. We are also working on a workflow that enables selections in live cells. 

If someone outside your lab wants to use the methodology, what is the best option? 

A) What do you need to provide them to make it work (select one or more)?
- Provide protocols/reagents (they can easily do it themselves) 
- Train a person from their lab
- You will likely need to perform the experiments in our lab, in collaboration

B) Is there any minimal expertise/equipment others need to work with the methodology?
- Library synthesis is easy, but needs basic organic chemistry expertise 
- Affinity selections per se can be performed anywhere
- Hit analysis requires specialized mass spectrometry (machines used for proteomics do work well)

Name one or more people in your lab that are experienced with the methodology
Edith van der Nol, Miguel Mata, Gianluca Turco, Jingming Liu, Monika Gnatzy

Who originally developed the methodology (provide reference if applicable)?
https://chemrxiv.org/engage/chemrxiv/article-details/682ee70b3ba0887c3336e338
https://chemrxiv.org/engage/chemrxiv/article-details/68da9353f416303770da0e1b
https://pubs.acs.org/doi/full/10.1021/jacs.3c04899

Additional information to provide:
Our self-encoded library (SEL) platforms make it easy to screen millions of small molecules and macrocycles without genetic barcodes or complex tagging. Using affinity selection tandem mass spectrometry, SEL and CycloSEL can find binders even to challenging targets, including nucleic acid–binding and protein-protein interactions. We’re looking forward to collaborate with biologists to apply this powerful approach to new targets and therapeutic areas.