Inside cells, proteins consistently interact with one another to perform different functions. For some diseases by which these functions are altered, blocking the binding between two or more proteins emerges as a possible therapeutic approach.

Scientists ​led by ICREA researcher Dr. Xavier Salvatella at IRB Barcelona have published guidelines for designing synthetic molecules that block the interaction between two proteins within the journal Nature Communications. Briefly, the researchers have focused on the interactions characterised by the binding of an α-helix of certainly one of the proteins on the surface of the opposite. This interaction mechanism could be very common and prevalent in cell functions of therapeutic interest related to diseases corresponding to prostate cancer.

The rules presented on this work allow scientists to develop molecules in a comparatively straightforward manner that block (potentially) any interaction between a globular protein and an α-helix, thus offering high versatility. These synthetic molecules also show high stability, are soluble in water, and may reach the inside of the cell. Such characteristics make them ideal drug candidates.

Our work proposes an easy approach to block interactions between globular proteins mediated by α-helices and it will probably profit each protein engineering and drug development efforts. It’s an approach based on research performed by our lab addressing the natural interactions of certain proteins, and it proposes using this data to attain therapeutic objectives through the design of small molecules with artificial sequences.”

Dr. Xavier Salvatella, Head of the Molecular Biophysics Laboratory at IRB Barcelona

Competition for a binding site

When two proteins “recognise” one another within the cell and interact, it’s because a region on their surfaces “matches”, thus allowing binding. The molecules addressed on this work, like many commonly used drugs, mimic this site on the surface of certainly one of the proteins involved within the Interaction, such that they “compete” to bind to the location of the opposite protein, which can also be known as the goal protein. Thus, if the competitor molecule is present at the next concentration or has a greater affinity for the goal protein, it is going to occupy all of the binding sites and block any possible interaction with the unique protein that the drug is mimicking. Nonetheless, the scale of enormous protein interaction interfaces makes it difficult to mimic the binding surface between them.

“What we propose on this work is to create molecules in the shape of α-helices that provide a configurable surface to “fit” the goal protein, and we explain how you can make sure that this helix maintains a stable structure within the cellular context,” explains Dr. Albert Escobedo, currently a postdoctoral researcher on the Center for Genomic Regulation (CRG), who led the work along with Dr. Salvatella at IRB Barcelona.

Describing the interactions and looking for a stable structure

The researchers have focused their efforts on detailing the characteristics that these synthetic molecules must meet to point out stability and have the opportunity to perform their function of inhibiting the interaction between two proteins. Within the study, they describe how several consecutive repetitions with a certain pattern of pairs of the amino acid glutamine and one other hydrophobic amino acid confer stability to the helix. In contrast to other approaches with the identical purpose, the exclusive use of natural amino acids and the absence of chemical modifications to stabilise the helix can enhance the biocompatibility and safety of the drugs designed using the brand new guidelines described.

In one other study published in Nature Communications in 2019, the researchers had already observed that, for a given protein, the variety of glutamine residues present within the structure condition the steadiness of its helix-shaped structure. On this latest study, they’ve confirmed that the identical thing also occurs in other proteins, they explain why and use the knowledge acquired to extend the flexibility of the molecules designed. Also, they propose how changes within the variety of glutamine residues present in several proteins could cause different diseases.

The work has been carried out in collaboration with the laboratory led by Dr. Modesto Orozco at IRB Barcelona and researchers from the Institute for Advanced Chemistry of Catalonia (IQAC), the Max Planck Institute for Biology, the University of Barcelona (UB), the University of Copenhagen, the López Neyra Institute of Parasitology and Biomedicine of the CSIC, and the CIC bioGUNE.

The study has been supported by the Spanish Association Against Cancer, the European Research Council (ERC), the Ministry of Science and Innovation (MICINN), and the Catalan Agency for the Management of University and Research Grants (AGAUR), the Novo Nordisk Foundation, and the National Bioinformatics Institute.

Source:

Institute for Research in Biomedicine – IRB

Journal reference:

Escobedo, A., et al. (2022) A glutamine-based single α-helix scaffold to focus on globular proteins. Nature Communications. doi.org/10.1038/s41467-022-34793-6.