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Alpha helix-shaped structure of one of the peptides designed in this study ( Image: IRB Barcelona).

Researchers at IRB Barcelona create a tool to block protein-protein interactions

Researchers at IRB Barcelona, based in the Barcelona Science Park, publish in Nature Communications guidelines for the design of new molecules with pharmacological potential for the treatment of a wide range of diseases, including prostate cancer. These peptidic molecules, which contain only natural amino acids, are easy to produce and show high biocompatibility and favourable pharmacokinetic properties.

Inside cells, proteins constantly interact with each other to carry out different functions. For some diseases in 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 in the journal Nature Communications. In brief, the researchers have focused on the interactions characterised by the binding of an α-helix of one of the proteins on the surface of the other. This interaction mechanism is very common and prevalent in cell functions of therapeutic interest related to diseases such as prostate cancer.

The guidelines presented in this work allow scientists to develop molecules in a relatively 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 can reach the interior of the cell. Such characteristics make them ideal drug candidates.

“Our work proposes a simple way to block interactions between globular proteins mediated by α-helices and it can benefit both protein engineering and drug development efforts,” explains Dr. Salvatella, head of the Molecular Biophysics Laboratory at IRB Barcelona. “It’s an approach based on research performed by our lab addressing the natural interactions of certain proteins, and it proposes using this knowledge to achieve therapeutic objectives through the design of small molecules with artificial sequences,” he adds.

Competition for a binding site

When two proteins “recognise” each other in the cell and interact, it is because a region on their surfaces “fits”, thus allowing binding. The molecules addressed in this work, like many commonly used drugs, mimic this site on the surface of one of the proteins involved in the Interaction, such that they “compete” to bind to the site of the other protein, which is also referred to as the target protein. Thus, if the competitor molecule is present at a higher concentration or has a greater affinity for the target protein, it will occupy all the binding sites and block any possible interaction with the original protein that the drug is mimicking. However, the size of large protein interaction interfaces makes it difficult to mimic the binding surface between them.

“What we propose in this work is to create molecules in the form of α-helices that offer a configurable surface to “fit” the target protein, and we explain how to ensure that this helix maintains a stable structure in the cellular context,” explains Dr. Albert Escobedo, currently a postdoctoral researcher at the Center for Genomic Regulation (CRG), who led the work together with Dr. Salvatella at IRB Barcelona.

» Reference article: Escobedo, A., Piccirillo, J., Aranda, J. et al. A glutamine-based single α-helix scaffold to target globular proteins. Nat Commun 13, 7073 (2022).

» More information: IRB Barcelona website [+]