Novel Drugs Offer New Route to Controlling

The team started by creating a three-dimensional map of a protein structure called the C3a receptor, which sits on the surface of human cells and plays a critical role in regulating a branch of the immune system called the complement system.

They then used computational techniques to design short portions of protein molecules, known as peptides, that they predicted would interact with the receptor and either block or enhance aspects of its activity. Finally, experimentalists validated the theoretical predictions by synthesising the peptides and testing them in animal and human cells.

The collaboration includes Christodoulos Floudas of the Princeton University, Dimitrios Morikis of the University of California, Peter Monk of the University of Sheffield, UK, and Trent Woodruff of the University of Queensland, Australia.

The regulation of the complement system – so called because it complements the body's central system of immune cells and antibodies – is thought to be a possible route to controlling over-active or mistaken immune responses that cause damage. However, few drugs directly target complement proteins, and none targets the C3a receptor, in part because of the complexity of the complement system. In some cases complement activity can help downplay immune responses while in other cases it can stoke even stronger reactions.

The collaborators were able to create peptides that blocked activity of C3a (antagonists) and others that stimulated it (agonists) with unprecedented potency and precision. Their success stems from a novel optimisation-based approach, developed in the Floudas lab, for computing how a protein's three-dimensional structure will change when changes are made in the protein's chemical sequence. This ability to design peptides of a desired shape, allowed them to target the C3a receptor in precise ways.

Morikis provided the collaborators the 3D structure of the naturally occurring peptide that normally regulates the C3a receptor in human cells. Using a portion of that structure as a flexible template, Floudas designed new peptides that were predicted either to enhance or block C3a. Monk tested the predictions in rat cells, while Woodruff tested them in human cells.; Source: Princeton University