Chemical biology makes precision medicines possible

Many types of medicine, including aspirin (a painkiller), plavix (an anticoagulant) and esomeprazole (an antacid), work by means of a permanent interaction with a protein in the patient’s body. The active ingredients get stuck there, as it were, switching off the function of the protein. This permanent blockade offers many advantages compared to medicines that do not cause such a blockade: the patient can get by with lower and less frequent doses.


An example of a recent application of the permanent-interaction concept comes from the successful Dutch biotech start-up AcertaPharma. Founded in 2012, the company has developed a new candidate medicine for the treatment of leukemia. The experimental drug ACP-196, a second-generation Bruton’s tyrosine kinase inhibitor, has proved very effective in patients with lymphomas. AcertaPharma was sold to AstraZeneca in 2015 for over EUR 4bn.


The permanent-interaction concept also has a few disadvantages, however. This type of medicine may cause more side effects, since the active ingredients can react with more than one protein at once, for example. A recent clinical study in France offered tragic evidence for this. One of the test subjects died during the testing of BIA 10-2474, a new experimental medicine, and three others became handicapped. A number of different proteins were permanently switched off while the drug was being delivered to the patients, leading to a neurological syndrome with severe complications.


To deal with this selectivity issue, chemical biologists at Leiden University have developed an innovative technology that enables them to determine the interaction partners of the experimental medicines at an early stage. With this technology, known as “activity-based protein profiling”, they have managed to trace the interaction partners of BIA 10-2474 in the human brain. Once it is known which proteins the active ingredient binds to, it is possible to make estimates of safe and effective doses. The Leiden researchers use the technology in collaboration with industry to develop new diagnostic techniques and drug candidates for deseases such as leukemia, Kahler’s disease, Gaucher’s disease, Fabry disease or neuroinflammatory diseases.