Targeting certain proteins, families of proteins and especially protein-protein interactions could inhibit their ability to develop into a range of diseases, including certain cancers, according to Ben-Gurion University researchers. The discovery could lead to groundbreaking preventative and therapeutic treatment methods, they said.
In a groundbreaking paper published in the October edition of Nature Communications, Dr. Niv Papo of BGU's Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and the National Institute of Biotechnology (NIBN),and incumbent of the Edgar de Picciotto Career Development Chair in Cancer Therapeutics and Imaging, said that current research on a wide variety of diseases, including some cancers, has implicated certain proteins in the development and progression of these diseases. Scientists therefore believe that observing the relevant interactions could open the way to developing new therapeutics and ultimately to understanding some of the mechanisms responsible of the development of such diseases.
“This is a major step in this direction," Papo said. “ By focusing on a protein family known as serine proteases, we demonstrated that it is possible to specifically target and inhibit two proteins (KLK6 and mesotrypsin) that are involved in cancer progression and other proteins (anionic and cationic trypsins) that are associated with the etiology of pancreatitis."
Papo explained that the research rests on scientists' ability to map the binding specificity landscape of interacting proteins, which is crucial both for fundamental science and for drug (inhibitors) development efforts. However, the limitations of currently available methods for mapping this landscape hinder the ability to develop specific inhibitors for clinically important proteins.
Overcoming those limitations has thus become the goal of Papo and his team, MSc student Si Naftali and PhD student Itai Cohen, in cooperation with crystallographers Anat Shahar, also of Ben-Gurion University and Prof. Evette Radisky of the Mayo Clinic, located Jacksonville, Florida.
The research team combined two cutting-edge techniques (multi-target selective library screening and in silico next-generation sequencing analysis) to provide an unprecedentedly rich analysis of the binding specificity landscape of proteins in a rapid, cost-effective process. Papo went on to say that his new approach would increase the understanding of the mechanisms and evolutionary origins of specific protein–protein interactions and facilitate the rational design of specific inhibitors that can discriminate between structurally similar protein targets.
Indeed, as many disease-related proteins belong to large families of related proteins, increasing target selectivity is a highly desirable but challenging goal in drug development.
“The new approach thus offers great promise for designing novel target-specific therapeutics," Papo said.