ReviewWhat makes a good anti-inflammatory drug target?
Section snippets
What makes a good anti-inflammatory target? – The basic principles
There are some basic principles that guide the discovery and development of successful therapeutic targets. First, the target might be proximal to the initiation of the disease – not necessarily the very first initiating event but at least close to it. Second, the target could play a pivotal or driving role in the disease process – these targets are often at key regulatory points or rate-limiting steps in pathways (so that blocking such an event stops a whole series of downstream processes).
Cytokines as drugs and drug targets
Cytokines are a large family of proteins, comprising ∼93 members and ∼96 receptors that are key signaling mediators in immune systems. Figure 2 shows the ‘total known cytokine world’ and how it is divided into distinct subfamilies. The term cytokine is reasonably well-defined – soluble proteins produced by leukocytes or other cell types that act as chemical communicators between cells. In some cases the term can encompass growth factors, such as epidermal growth factor, transforming growth
Interleukins as drugs and drug targets
We can get a more detailed measure of the success and/or failure rates of cytokines by analyzing one of the subfamilies, the interleukins. Interleukins are cytokines that are largely, but not exclusively, produced by T cells, which are key cells involved in initiating and controlling immune responses. Hence, the T-cell-derived cytokines are likely to be pivotally important in inflammation. Interleukin (IL) numbers (e.g. IL-1) have been assigned in chronological order of discovery. It is
Adhesion molecules and CSMs
Adhesion molecules and CSMs play distinctive roles in inflammatory processes. Cell adhesion molecules (CAMs) are key players in mediating leukocyte migration from the vasculature blood stream to sites of inflammation and then leukocyte re-circulation to the lymphatic system and lymphoid organs. CAMs form specific pairings of receptors and ligands expressed on adjacent cells, leading to either transient or sustained intercellular adhesion. In addition, some CAMs link cells to the extracellular
GPCRs
GPCRs are integral membrane proteins characterized by having seven trans-membrane domains and also because they engage intracellular G proteins to initiate signaling cascades, upon ligand binding.
In many diseases they are a drug-dense family, particularly in the neuroscience and cardiovascular fields. Surprisingly, in the field of inflammation, GPCRs have yielded a relatively small number of validated drug targets. However, these targets have produced multiple, individual approved drugs that
Conclusions
This review has focused on using a combination of guiding principles (that define a good anti-inflammatory target) and an analysis of the approved anti-inflammatory drugs, making some rational statements about the future sources of new candidates.
To recap, the guiding principles that define good anti-inflammatory targets are: first, they are proximal to the initiation of the disease process; second, they are crucial to the driving force of the cascade; and third, they are specific to the
Acknowledgements
I would like to thank Mary Collins at Wyeth for Figure 2.
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