| Ann-Christin Malmborg Hager and Christina Furebring at Alligator Bioscience AB and Philippe Stas at AlgoNomics look at a growing trend for resuscitating abandoned clinical trials
Developing pharmaceuticals is a risky business, involving enormous costs. While pharmaceutical companies invest heavily in those molecules they believe in, a failure during the development process can be very damaging. According to several reports, only 10 per cent of drug candidates entering the preclinical phase will reach the market; what happens to the rest? Do the remaining 90 per cent that do not make it to the market forever inhabit the drug companies’wastepaper baskets? This article discusses a project that is put back on track after a failure in Phase I.
THE CHIPS PROTEIN
The drug candidate in question was chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) (1). The protein was discovered by the research group of Jos van Strijp, Professor of Microbiology at the Eijkman Winkler Institute in Utrecht, the Netherlands.
When bacteria enter the human body they are surrounded by human proteins. One of these proteins is C5a, a component of the complement system. C5a binds to the C5a receptor (C5aR), which is found on the surface of, for example, neutrophils, a very important cell type in the innate immune system. This activates the neutrophils, while stimulating chemotaxis so that more inflammatory cells are recruited to the site of infection.
To protect themselves, bacteria – in this case Staphylococci – develop mechanisms to prevent themselves from being destroyed by the recruited neutrophils (2). One mechanism used by Staphylococci is the production of a 14kD protein (the CHIPS protein) that downregulates the ability of C5aR to bind its ligands, by blocking the binding site of C5a. This blocks neutrophil chemotaxis.
The plan was to use CHIPS, with its anti-inflammatory effects, as a drug, preventing the progression of neutrophil-mediated inflammation that gives rise to and aggravates disease symptoms. In indications involving acute cases of inflammation, the effects of CHIPS could be beneficial, and at present there are no drugs on the market for such indications. The mechanism of CHIPS´ antiinflammatory ability is schematically outlined in Figure 1. |
