Medicinal Chemistry

The Structure and Inhibition of Calpains

The movement of white blood cells, especially neutrophils and lymphocytes, from the blood to the tissues is the key event underlying inflammation. Understanding the mechanism by which these cells adhere to the cells lining the blood vessels is clearly important, as this would be a potential target for anti-inflammatory therapy. Research at Cardiff has found that changes in the concentration of Ca2+ within the cells is crucial for this and there is increasing evidence that the Ca2+-activatable protease calpain-1 is also involved. There is good evidence that calpain-1 mediates cell shape change (eg cell adherence, extravagation and phagocytosis) signaled by cytosolic Ca2+ in immune cells. However, experimental progress is hampered by the lack of a specific calpain-1 inhibitor, and possibly confused by the use of non-selective cysteine protease inhibitors.

Analogues of PD151748

Figure 1. Analogues of the existing calpain inhibitor PD151746 are readily synthesised from 3-carboxyindoles.

In collaboration with Prof. Maurice Hallett in the Cardiff Medical School this project aims to develop compounds based on PD151746 (the most selective calpain-1 inhibitor reported to date) that are potent and selective inhibitors of calpain-1, permeate cells, and are not cytotoxic. Such inhibitors would be useful for the scientific community and accelerate our understanding of calpain-1. Furthermore, such compounds may be useful as treatments of diseases such as rheumatoid arthritis.

PDB strutures 4WQ2 and 4WQ3

Figure 2. Monomeric (left, PDB: 4WQ2) and dimeric (right, PDB: 4WQ3) 6-bromoindole inhibitors bound to the PEF-(S) domain of human calpain I.

Selected publications:
• Sarah E. Adams, Emma J. Robinson, David J. Miller, Pierre J. Rizkallah, Maurice B. Hallett and Rudolf K. Allemann, Chemical Science, 6, 6865-6871 (2015). DOI:10.1039/C5SC01158B.
• Sarah E. Adams, Pierre J. Rizkallah, David J. Miller, Emma J. Robinson, Maurice B. Hallett, Rudolf K. Allemann, J. Struct. Biol., 187, 236-241 (2014). DOI:10.1016/j.jsb.2014.07.004.
• Sarah E. Adams, Christian Parr, David J. Miller, Rudolf K. Allemann and Maurice B. Hallett, MedChemComm., 3, 566-570 (2012). DOI:10.1039/C2MD00280A.