A new path toward disrupting disease

Researchers are assembling a library of molecules that may treat diseases by interfering with interactions between proteins

A new target for treating disease may be lying inside our cells just waiting to be attacked. Many conventional drugs target protein molecules by affecting the site of a protein’s activity directly. Yong-Dae Gong and colleagues at Dongguk University in Korea are working toward a very different approach—disrupting the interactions between much larger parts of protein surfaces.

Protein–protein interactions (PPIs) between protein molecules can play a major part in protein activity, yet they are poorly understood. “So far, only a minimal fraction of the estimated 650,000 protein–protein interactions in our cells are known,” says Gong. This offers a rich uncharted territory that he and others believe may open up a new frontier in drug development.

To affect PPIs, molecules must generally be larger than most drugs. They need to interact extensively with parts of the surface of a protein rather than fitting into one small site. As a first foray into this territory, Gong’s team are using core molecules called oxadiazoles, with longer structures mimicking segments of proteins called peptides attached to this core. They report their progress in the journal Tetrahedron. “This is just the first step in the long path of drug development,” says Gong.

Gong’s main research specialty is making small “heterocyclic” molecules that contain rings of atoms, in search of new drugs. When he recently became interested in PPIs, he realized that one class of his heterocyclics—the oxadiazoles—had the potential to carry the peptide-mimicking branches needed to interfere with the interactions. He is therefore creating a “library” of oxadiazole-based compounds with PPI-interfering possibilities.

The chemistry needed to create these compounds has some novel aspects, but according to Gong “the main challenge is in studying the biological activities and mechanisms of the drug-protein interactions.”

In the meantime, the team are continuing to expand their library of potential PPI-interfering compounds. They want to generate an ever-greater variety of structures, including some that more closely mimic the specific sections of proteins they wish to interfere with.

It is too early to point to any specific conditions that this unconventional approach may treat, but the rewards for opening up a new angle of attack on disease could be huge. “I believe that there is a lot for us to discover in the future,” Gong says.

The methods the researchers are using to develop their own compounds may also spur others to venture into the territory of PPI-interference. A few years from now a new vista of therapeutic possibilities may open up, thanks to pioneers like Gong.

Abdildinova, A., Yang, S-J. & Gong, Y-D. et al.: "Solid-phase parallel synthesis of 1,3,4-oxadiazole based peptidomimetic library as a potential modulator of protein-protein interactions," Tetrahedron(2017)