Double Duty Inhiitor?

REFERENCE: Hansen et al. Structure (2011) 19, pgs 919 – 929.

Malaria, a disease that causes 1 million deaths per year, is caused by a Plasmodium parasite.  Cysteine proteases (CPs) expressed by the parasite are implicated in key process of both parasitic life stages: liver and blood.  Interestingly, host cell CPs are also integral to infection.  Given the destructive nature of proteases, CPs of both host cells and parasites must be regulated site-specifically and temporarily.  In the July issue of Structure, Hilgenfeld and colleagues discuss the structure of the Plasmodium cysteine protease falcipain-2 (FP-2) in complex with the C terminus of their identified CP inhibitor from Plasmodium berghei (PblCP-C).  PblCP-C has an Ig-like ß sandwich fold and its closest structural relative is identified as chagasin, an I42 inhibitor family member.  Loops L0, L2, L4, and L6 protrude from PblCP-C (shown) into the active site of FP-2, thus occluding substrate binding.  The authors compare the PblCP-C:FP-2 structure to other solved inhibitor complexes and conclude that the major interactions responsible for inhibition are conserved between the structurally unrelated inhibitors, but the PblCP-C L0 interactions with FP-2 are unique to this complex.  Intriguingly, the structure of L0 also explains why PblCP-C is a potent inhibitor of the papain-like protease cathepsin L but not cathepsin B.  Because PblCP is necessary for host cell invasion, it is postulated that this CP inhibitor could block potentially deleterious protease activity at crucial moments, such as host-cell invasion, or inhibit host cell CPs (such as the cathepsin-like caspases).  It also provides a framework for developing small molecule inhibitors of the critically important FP-2.