Cancer researchers develop method to streamline treatment for diseases

‘By using our method, the time frame for generating the drug can now be much shorter.’

Ben-Gurion University of the Negev's Dr. Niv Papo (photo credit: DANI MACHLIS / BGU)
Ben-Gurion University of the Negev's Dr. Niv Papo
(photo credit: DANI MACHLIS / BGU)
What if researchers had better chance of choosing the right protein mutation, and were able to cut drug development time to combat certain illnesses and diseases? A team of cancer researchers, headed by Ben-Gurion University of the Negev’s Dr. Niv Papo, and Hebrew University of Jerusalem Prof. Julia Shifman, are working to do just that.
The cancer researcher need to understand the relationships created by cellular proteins, especially the mutations that occur when those relationships go awry, in other words, mutate.
A joint statement from the two universities explained that with thousands of potential mutations for every protein to protein interaction (PPI), “the process was costly, labor-intensive and time-consuming.”
Prof. Julia ShifmanProf. Julia Shifman
Existing technologies have allowed scientists to observe only one mutation at a time, and each observation can take several weeks to months to do.
“As a result, researchers would spend months constructing protein mutants and measuring their effect on binding affinity (the strength with which proteins interact with their target proteins in cells), slowing down the study of how and why diseases progress,” the universities said.
The team has developed a powerful tool to simultaneously evaluate thousands of mutations in protein to protein complexes and to map their effect on protein binding affinity, turning a process that could take years into one that takes just a few days.
“We generate a protein library in which each member of the library carries a single mutation in the protein so that the entire library consists of millions of different protein mutants (each mutant differ in a single amino acid from the rest of the mutants),” Papo told The Jerusalem Post.
He said that they then screen this protein library against the target protein, which is a different protein than the one in the library.
“The target protein is a protein that is disease related and we want to find mutants that will bind to it and inhibit it,” he explained. “From these screens we isolate and sequence, using deep sequencing technology, all the mutants that have high affinity and determine the frequency in which each of the mutants appears in the high affinity pool of mutants.”
Papo added that this is how they can give a score to each mutant according to its ability to bind and inhibit the target.
“Mutant proteins with high scores,i.e. high affinity to the target, can now be used as potent drugs against their targets, which are disease related proteins,” he said.
According to Papo, their method also allows the identification of mutations that happen in disease related proteins.
“The method allows us to screen millions of such mutations and determine which ones of these mutations affect the affinity of the disease related protein to its target,” he continued. “Knowing this allows us to develop inhibitors against these specific disease-related protein mutants and it also to understand the mechanism of disease progression,” meaning what protein mutations are causing the disease.
This means that the time frame for generating the drug can now be much shorter “by using our method.
“We can easily and very quickly identify and isolate protein-based drugs that have strong binding affinity (and specificity) and inhibition potency towards the disease related target,” he said.
Asked for examples, Papo said that this includes cancer-related protein targets.
“We were able to show that we can identify and isolate and generate a protein mutant that has extremely strong affinity and ability to inhibit the cancer related target protein,” he explained. “This cancer-related target protein is a protease that is highly expressed in many types of cancers and facilitates cancer cell invasion in the body the formation of distant metastasis in different organs in the body.
“Our protein mutant can block the pro-metastatic activity of this cancer related protease,” Papo stressed.
He also highlighted that strong protein binders can also be used as excellent diagnostic agents in cancer, adding that different cancers have different profiles of expression of protein targets, known as antigens.
“Our method allows to generate very strong binders to these antigens and by labeling our strong binders with dyes or radioisotopes, these binders can serve as excellent diagnostic agents in the clinics,” Papo concluded.
Shifman explained that, "Just like people, proteins maintain ‘social networks.'
“Some ‘couples’ partner for the long-term, while others prefer numerous and  promiscuous interactions, she said. "When the proteins act the way they are supposed to, the body is healthy. But when the binding affinity becomes affected – that is, when stable relationships break up too quickly, or fleeting ones fail to disengage – that’s when disease happens.“
According to the universities, this development is an important step for both applied and theoretical scientists.
“Currently in the pharmaceutical industry, most of the promising new drugs in production are proteins that destroy certain disease-associated protein-protein interactions,” the statement said, stressing that this “new method of quantifying the effect of thousands of mutations allows researchers to design protein drugs that are both potent and specific, causing minimal side effects.”
Their findings were published on Wednesday in Nature Communications.