Universiteit Leiden

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Daniel Weinbuch

Two-pronged attack on infectious diseases

A combination of two potential drugs gives hope of a 'super blockage' of an over-active immune system, Leiden researchers report in Nature. The breakthrough came from the crystallisation of a membrane protein.

Over-alert immune system

Our immune system is intended to protect the body against infiltrators. But sometimes it behaves too alertly, attacking the body itself. This results in chronic inflammation, such as multiple sclerosis, rheumatism or osteoarthritis. 

Inhibiting inflammatory reactions

Laura Heitman, Ad IJzerman, Henk de Vries and Natalia Ortiz Zacarias from the Leiden Academic Centre for Drug Research (LACDR) are publishing their research this week in the journal Nature, research that may lead to a more effective way of inhibiting these responses. Their research focuses on the CCR2 receptor. The Leiden researchers work closely with an American team headed by Tracy Handel and Irina Kufureva.

Keyhole at nanoscale

A receptor is a kind of keyhole at nanoscale on the outside of a cell - in the cell membrane - into which a specific key molecule fits. The immune system comprises all kinds of immune cells, each with different types of receptors. The key molecules are called chemokines, and are produced by cells in diseased tissue. Immune cells are attracted automatically towards higher concentrations of chemokine, which generally means towards parts of the body where they are needed.  

Inhibitors ineffective

But patients with rheumatism or osteoarthritis produce too much CCL2, the chemokine for the CCR2 receptor. Although there are ways of blocking the CCR2 receptor, which in turn inhibits the inflammation, the inhibitors currently available prove to be largely ineffective in humans.      

Protein crystallisation

In order to discover how this process works at atomic level, Heitman and her colleagues examined the CCR2 protein using X-rays. This cannot be done using whole cells or a fragment of the cell membrane, where other proteins are also present. The researchers needed to have the CCR2 protein in very pure crystal form. This had never previously been done successfully. Laura Heitman: 'If you take this kind of protein from the cell membrane, it's very difficult to crystallise it.' 

Thanks to this advance, researchers now have a detailed understanding of the three-dimensional form of the CCR2 protein, which is a good starting point for further research on the interaction beteween CCR2 and the related CCL2 chemokine.The research had immediate results: crystallisation was only possible if two inhibitors (BMS-681 and CCR2-RA-[R]) are both added to the CCR2 protein.

Possible duo medicine

Heitman: 'This suggests a new strategy:  duo therapy. By administering these two substances at the same time, you get a kind of "super blockage" of the CCR2 receptor, which is more effective than administering the two substances separately.' Heitman refers to these substances deliberately as 'potential medicines': this is just the start of a process that could lead to a new duo medicine. 

Other receptors 

Heitman's group will first continue their work with other receptors, CCR1 and CCR3 up to and including CCR9 before considering other super inhibitors. The ultimate aim is to manipulate the immune system so effectively that it only has beneficial effects, and the detrimental effects are excluded.   

 

Article in Nature

Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

Yi Zheng, Ling Qin, Natalia V. Ortiz ZacarĂ­as, Henk de Vries, Gye Won Han, Martin Gustavsson, Marta Dabros, Chunxia Zhao, Robert J. Cherney, Percy Carter, Dean Stamos, Ruben Abagyan, Vadim Cherezov, Raymond C. Stevens, Adriaan P. IJzerman, Laura H. Heitman, Andrew Tebben, Irina Kufareva & Tracy M. Handel