Broad-spectrum Chemokine Inhibitors (BSCIs)
Why chemokines?
One of the long term aims of the Inflammation Research and Therapy Laboratory has been to understand the mechanisms which control macrophage recruitment to sites of inflammation. Macrophages are important leukocytes (white blood cells) which patrol most tissues looking for foreign bodies such as bacteria. One of the earliest stages in chronic inflammation, which is a component of a range of important diseases such as atherosclerosis, Alzheimer's disease, osteoporosis, autoimmune disorders and so on, is recruitment of additional macrophages to the inflammed area.
In 1999, Jill Reckless in the group published an important paper (Circulation 99:2310) which aimed to exploit an interesting observation made by David Grainger a number of years previously: transgenic mice which over-express apolipoprotein(a) develop lipid lesions resembling human atherosclerosis but which lack any macrophage recruitment. In collaboration with Prof. Eddy Rubin and colleagues at UC Berkeley, we compared apo(a) transgenic mice with another mouse line which develops lesions rich in macrophages. By systematically comparing the levels of a range of cytokines in the lesions from these two groups of mice we hoped to uncover which cytokines might play a crucial part in macrophage recruitment during the development of athrosclerosis. The vast majority of cytokines were similar between the two groups of mice, but there was one noticable exception - the chemokine MCP-1.
Chemokines are a range of 8-12 kDa signalling proteins which are involved in the regulation of the immune system both in normal physiology and in a range of pathologies. The most important function of chemokines seems to be in regulating the trafficking of leukocytes from one site in the body to another. It was, perhaps, not surprising therefore to discover that this particular chemokine was missing in mice deficient in macrophage recruitment, but present where macrophage recruitment occurred normally. At about the same time that we uncovered this correlation, Boring and colleagues (Nature 394:894) and Gu and colleagues (Mol Cell 2:275) demonstrated that genetic ablation of MCP-1 signalling reduced macrophage accumulation in lipid lesions in mice. Together with our work, these studies strongly implicated chemokines in the regulation of pathologic macrophage recruitment during atherogenesis.
Back in 1998, when these studies were in progress in the laboratory, hardly any drug molecules had been described which could be used as chemokine inhibitors to test whether chemokine blockade would be a useful therapeutic approach in athrosclerosis. This was a surprising situation: chemokines signal through receptors which are members of the large superfamily called G-protein coupled receptors (or GPCRs). GPCRs have generally yielded easily to the familiar high throughput screening methodology of large pharmaceutical companies and a very significant number of successful human drugs target GPCRs effectively. Yet despite a concerted effort from a range of companies, good chemokine receptor antagonists had not emerged. So we began a programme of our own to find a chemokine inhibitor, using a novel approach ...