Plasma kallikrein is an important intrinsic pathway serine protease that cleaves kininogen to generate the peptide bradykinin. Bradykinin causes local inflammation increasing pain and swelling. Hereditary angioedema (HAE) is a genetic condition of artificially low plasma C1 Inhibitor levels leading to overactivity of the intrinstic pathway and excessive production of bradykinin. HAE attacks are characterized by painful giant swelling of the mucosal tissues of the upper respiratory and gastrointestinal tracts. Kallikrein is a proven target for treatment of HAE as well as hyperglycemia-induced retinopathy and other related inflammatory disorders.
Molecular Innovations purified prekallikrein from horse plasma and activated it to horse kallikrein to fulfill a custom request for Global Blood Therapeutics. Horse kallikrein shares greater than 80% protein sequence homology with human kallikrein but has an asparagine residue instead of glycine at amino acid position 480. Scientists at GBT postulated that binding location was the key to the more specific kallikrein inhibition of a small molecule patented by Novartis compared to Avoralstat which has affinity for a range of serine proteases. Indeed, Avoralstat inhibited both horse kallikrein and human kallikrein in an amidase activity assay while the Novartis coumpound only inhibited human kallikrein.
Human kallikrein from Molecular Innovations was also used for crystallization in this paper. It was co-crystallized with the Novartis compound and solved at a resolution of 2.2 Å. This is a strong statement for the quality of Molecular Innovations products since only the most pure proteins can be successfully crystallized.
The following Molecular Innovations products were used in this publication:
Molecular Innovations is the only commercial manufacturer of Horse Kallikrein. We also offer Horse Prekallikrein, a full selection of coagulation factors and plasma proteins, and perform custom projects.
Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition. James R. Partridge, Rebeca M. Choy, Abel Silva-Garcia, Chul Yu, Zhe Li, Hing Sham, Brian Metcalf. Received 16 November 2018, Revised 28 February 2019, Accepted 1 March 2019, Available online 12 March 2019.