Attaching polypeptides to small molecules can significantly increase the specificity and affinity of protein binders

Researchers in Sweden have found a way to boost the specificity of drugs and other protein binders. The method, which involves attaching polypeptides to the binders, could help reduce the work required to develop protein binders into safer drugs.

Almost all drugs are protein binders. They work by interacting with certain proteins so that the proteins’ functions are blocked or stimulated, depending on the effect required. Protein binders are also used in medical diagnostics, industrial protein purification and many other areas of biotechnology and bioanalytical research. 

"We cut out much of the work in between a lead and a drug" - Lars Baltzer, Uppsala University, Sweden

The problem, however, is finding binders that target only specific proteins, since targeting others could result in toxic effects. Drugs (’synthetic’ protein binders) tend to be small, and therefore have few chemical ’handles’ to bind with. This means there is always a risk a potential drug will interact with proteins other than those intended. Moreover, proteins can change shape once they interact with a drug, thereby opening themselves up to interaction with other binders. 

The result is that many protein binders thought to be effective drugs fail once researchers realise their interactions are not specific enough. ’Nineteen out of twenty small molecule projects are cancelled in big pharma due to unexpected toxicity or poor effect, which are both signs of limited specificity in the human body,’ says Lars Baltzer of Uppsala University.

Now, Baltzer and his colleagues may have found a way around this problem. They take a smaller protein binder and link it to a set of polypeptides, each of which has many possibilities to interact with a protein. In this way, a protein binder that has just 10 possible groups to interact with a protein can be modified to have over 50, vastly increasing its specificity. 

According to Baltzer, this gives researchers a shortcut in developing a protein binder into a successful drug. ’The last steps to improve the drug from a "lead" to a "candidate" and finally a drug cost a lot, but the identification of a lead is relatively straightforward,’ he says. ’We simply cut much of the work in between lead and drug.’

Andrew Wilson, a chemist specialising in protein binders at the University of Leeds, UK, says the work is ’quite nice’, but notes there are other technologies to improve binding specificity. ’What is impressive is that the enhanced binding seems to be observed with a comparatively small set of diverse polypeptides - I would not have predicted this,’ he says.

Jon Cartwright