Within the cell, proteins continuously interact with each other to perform different functions. For some diseases where these functions are altered, blocking the binding between two or more proteins becomes a possible treatment.

Dr. Xavier Salvatella, a scientist led by ICREA researchers, published guidelines for the design of synthetic molecules to prevent interactions between the two proteins in Nature Communications. In short, researchers focus on the interaction of one protein with the alpha helix on the surface of another protein. This mechanism of interaction is very common and prevalent in cellular functions of therapeutic interest associated with diseases such as prostate cancer.

The guidelines presented in this work allow scientists to develop molecules in a relatively straightforward way that blocks any interaction between (potentially) globular proteins and α-helices, thus providing high versatility. These synthetic molecules also exhibit high stability, are soluble in water, and reach the interior of the cell. These properties make them ideal candidates.

Dr. Salvatella, head of the Molecular Biophysics Laboratory at Barcelona IRB, explained: “Our work suggests a simple way to prevent interactions between spherical proteins mediated by the alpha helix, which is beneficial for protein engineering and drug development. This is a method based on research performed in our laboratory that addresses the natural interactions of certain proteins and proposes to use this knowledge to achieve therapeutic goals by designing small molecules with artificial sequences.”

When two proteins “recognize” each other and interact with each other in the cell, it is because a region on their surface “fits” and thus allows binding. Molecules processed in this work, like many commonly used drugs, mimic this site on the surface of one protein involved in the interaction, so that they “compete” to the site of another protein, which is also called the target protein. Thus, if a competitor molecule is present at a higher concentration or has a stronger affinity for the target protein, it will occupy all binding sites and prevent any interaction with the original protein that may be mimicked by the drug. However, the size of large protein interaction interfaces makes it difficult to model the binding surface between them.

Dr. Albert Escobedo, currently a postdoctoral researcher at the Center for Genomic Regulation (CRG), led the work with Dr. Salvatella of the IRB in Barcelona, explaining: “What we propose in this work is to create molecules in the form of alpha helices that provide a configurable surface to fit the target protein and explain how to ensure that this helix remains stable in the cellular environment.”

Researchers focused on detailing the properties that must be met by these synthetic molecules in order to show stability and be able to perform functions that inhibit the interaction between the two proteins. In this study, they describe how successive repeats of specific pairings of several amino acids glutamine and another hydrophobic amino acid stabilize the helix. The complete use of natural amino acids and the absence of chemical modifications to stabilize the helix could enhance the biocompatibility and safety of drugs designed using new guidelines compared to other methods with the same objective.

In another study published in Nature Communications in 2019, researchers have observed that for a given protein, the number of glutamine residues present in the structure impacts the stability of its helical structure. In this new study, they confirm that the same thing happens in other proteins, and they explain why, and use the acquired knowledge to increase the versatility of the designed molecule. In addition, they proposed how changes in the number of glutamine residues in different proteins lead to different diseases.

Collected by Profacgen. We have established in our lab a series of assays to help with protein interaction analysis research, including high throughput interaction screening assays such as Yeast two-hybrid screening and phage display technology, interaction strength and kinetics assays such as Surface Plasmon Resonance (SPR).