Mass spectrometry reveals the process of protein ‘glues’

In this file photo taken on January 27, 2021, Palestinian doctors and technicians work at the IVF laboratory at the Razan Center fertility clinic in Nablus, in the Israeli-occupied West Bank – Copyright AFP/File Jaafar ASHTIYEH

Researchers from the University of Birmingham (U.K.) have applied an established screening technique called mass spectrometry, which is commonly used in drug discovery, to examine more about the nature of proteins. Specifically, the inquiries have uncovered details about the actions of molecular ‘glues’ in protein interactions.

Targeted protein degradation is a promising area in the discovery and development of innovative therapeutics. Molecular glues are powerful therapeutic tools, capable of sticking proteins together in the human body. The interactions between proteins are essential and they underpin all biological cell functions. This includes disease; therefore, understanding and controlling protein-protein interactions will carry a significant potential for disrupting the progress of various diseases.

As well as seeking to interrupt the processes that connect proteins together, there are occasions when interventions are required to restore an interaction.

Mass spectrometry is an analytical tool useful for measuring the mass-to-charge ratio (m/z) of one or more molecules present in a sample. The technology measures the mass of a molecule once it converts the molecule to a gas-phase ion. This happens by imparting an electrical charge to molecules and this converts the resultant flux of electrically charged ions into a proportional electrical current. The resultant information is captured and read by a computerised data system.

In particular, native mass spectrometry can detect multiple protein species simultaneously, providing scientists with a point of entry in order to elucidate the protein mechanisms.

According to lead researcher Dr Aneika Leney: “Often when we are designing new drugs, it is to stop harmful protein interactions in the body, such as those that lead to tumour cell growth in cancers. Sometimes, however, the disease is caused by protein interactions falling apart and in these cases finding the right glue to hold them together could be extremely beneficial.”

The most important insight so far concerns a molecular glue called MG1. By using the mass spectrometry method, the researchers have succeeded in disentangling the different mechanisms through which the glue is bound to the proteins. Furthermore, the researchers managed to stabilise the protein interaction.

The mass spectrometry method allowed the researchers to elucidate the relative time taken by the different processes involved. This should help medical researchers to better design and build the next generation of molecular glue drugs.

The research appears in the journal Chemical Science. The paper is titled “Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry.”