High throughput spectral shift: an exciting breakthrough in drug discovery

Vanessa Porkolab, Biophysics Director, Eurofins Discovery; Céline Legros, Business Line Leader, Target Validation, Hit Finding & Hitto-Lead; hitfinding@discovery.eurofinseu.com

A novel affinity-based screening method, High Throughput Spectral Shift (HT-SpS), was recently implemented at Eurofins Discovery for Hit Finding programmes. With its unprecedented throughput and
use of direct biophysical measurement, HT-SpS enables the identification of binders that would be missed during conventional High Throughput Screening (HTS). It provides a valuable alternative to Affinity Selection-Mass Spectrometry (AS-MS) and DNA-encoded Library (DEL), making high-throughput, site-agnostic binding approaches achievable with a very small amount of the tested target, no data deconvolution, and with no need for compound multiplexing.

This new method is Eurofins Discovery experts’ latest tool to support clients in the Hit Finding step of their drug discovery journey. Hit Finding, essential to identifying the chemistry starting point for future lead compounds & candidates, can be addressed using several approaches, including HTS, i.e. the screening of hundreds of thousands of compounds in robust and miniaturised assays, allowing the identification of modulators (activators/inhibitors) and site-agnostic binders. Binders play an important role in affinity-based drug discovery because they help identify and optimise potential drug candidates. By understanding how a binder interacts with its target, researchers can design more effective and selective drugs.

HT-SpS is performed using the NanoTemper^® Dianthus uHTS, a second-generation screening platform using Spectral Shift technology. Spectral Shift is achieved through dual-wavelength measurements in an isothermal environment. Compared to a conventional activity-based HTS, this affinity-based screening uses the “whole” protein. HT-SpS is highly sensitive and works with a variety of molecular modalities, including fragments, small molecules, peptides, macrocycles, nucleic acids, and degraders, including molecular glues. This provides a highly versatile solution that can support clients working on a wide range of therapeutics. For example, it is ideal for Targeted Protein Degradation research as it helps identify site-agnostic binders that are crucial for developing novel degraders.

Furthermore, HT-SpS requires only hundreds of micrograms of protein for a screening project, maximising resources while maintaining a screening efficiency of 65,000 data points per day. This allows biotech and pharma companies with difficulties in target production to access precision even if they only have a very small amount of protein available. In addition, several protein labeling strategies are possible, depending on the protein construction and target specificity. Eurofins Discovery and Eurofins DiscoverX^® have the technologies and expertise in recombinant, soluble, and membrane protein production to meet these challenges.

Thanks to Eurofins Discovery’s expertise in biophysics & HTS and this novel technology, a door has opened to previously unexplored chemical space, enabling the discovery of hits that can lead to groundbreaking advancements in drug development. As the first Contract Research Organisation to offer this revolutionary service, Eurofins Discovery is proud to stay at the forefront of screening technology and rapidly provide early insight into mechanisms of action, as well as to address difficult or undruggable targets. For more information, visit: www.eurofinsdiscovery.com/solution/biophysical-assays