Traditional discovery has produced drugs that effectively target proteins directly involved with disease, but options are starting to run out and researchers are looking to more complex and obscure interactions for drug targets.
So far, drug discovery has used the ‘small molecule’ approach, where a specific protein is targetted in a cancer cell to shut it down and bring down the cancer cell as a whole. Up until this point, traditional drugs have only been able to target proteins that are involved in the disease that also have activities that are amenable to the small molecule approach, leaving a vast number of proteins unaddressed. Many of these other proteins may be involved in disease processes behind the scenes.
“It’s starting to get to the point where we’ve kind of taken traditional drug discovery as far as we can, and we really need something new,” explained University of Nevada, Las Vegas biochemist Gary Kleiger.
“Cancer cells are clever,” Kleiger said. “They can evolve very, very quickly. So, a drug might be working at first—targeting an enzyme and telling that enzyme, ‘stop doing your activity,’ which can stop the cancer cells from growing. Those cancer cells appear to lie dormant, but all the while there are still little things that happen that eventually enable those cancer cells to bypass that drug.” Therefore, in order to stay ahead of cancer’s capacity to evolve drug resistance, it is necessary to target many additional disease-causing proteins, and thus, limiting the landscape of druggable proteins is a serious disadvantage.
The new approach by investigated by Kleiger and collaborators uses a family of human enzymes called ubiquitin ligases found in human cells. Of about 20 000 known proteins in the human body, some 5-10% are enzymes.
Kleiger’s team uses cutting edge cryo electron microscopes that can image the ubiquitin ligases when they’re at work. To test their hypotheses, Kleiger and collaborators measure the activity of ‘mutated’ enzymes that should now be defective in their activities.
Kleiger compared the process to how a 50 000 year old society might view a bicycle. They could identify its purpose and general properties, but could test the importance of a certain gear; if it was bent, the bicycle would no longer function. “We can do that at the molecular level with the enzymes,” he said.
Source: Medical Xpress
Journal information: Daniel Horn-Ghetko et al, Ubiquitin ligation to F-box protein targets by SCF–RBR E3–E3 super-assembly, Nature (2021). DOI: 10.1038/s41586-021-03197-9
