7N7X

Crystal structure of BCX7353(ORLADEYO) in complex with human plasma kallikrein serine protease domain at 2.1 angstrom resolution

This is a non-PDB format compatible entry.

Summary for 7N7X

• Entry DOI: 10.2210/pdb7n7x/pdb
• Related: 2ANW 2ANY 5tjx
• Descriptor: Plasma kallikrein light chain, Orladeyo, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: kallikrein, blood, plasma, plasma kallikrein-mediated edema, acute hereditary angioedema, hae, hmwk, hereditary angioedema, haw, bradykinin, fletcher factor, kininogenin, serine protease, edema, orladeyo, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 27326.90

Authors

Krishnan, R.,Yarlagadda, B.S.,Kotian, P.,Polach, K.J.,Zhang, W. (deposition date: 2021-06-11, release date: 2021-09-15, Last modification date: 2024-11-20)

Primary citation

Kotian, P.L.,Wu, M.,Vadlakonda, S.,Chintareddy, V.,Lu, P.,Juarez, L.,Kellogg-Yelder, D.,Chen, X.,Muppa, S.,Chambers-Wilson, R.,Davis Parker, C.,Williams, J.,Polach, K.J.,Zhang, W.,Raman, K.,Babu, Y.S.
Berotralstat (BCX7353): Structure-Guided Design of a Potent, Selective, and Oral Plasma Kallikrein Inhibitor to Prevent Attacks of Hereditary Angioedema (HAE).
J.Med.Chem., 64:12453-12468, 2021

PubMed Abstract: Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50 000 individuals worldwide. Until recently, prophylactic HAE treatment options were limited to injectables, a burdensome administration route that has driven the need for an oral treatment. A substantial body of evidence has shown that potent and selective plasma kallikrein inhibitors that block the generation of bradykinin represent a promising approach for the treatment of HAE. Berotralstat (BCX7353, discovered by BioCryst Pharmaceuticals using a structure-guided drug design strategy) is a synthetic plasma kallikrein inhibitor that is potent and highly selective over other structurally related serine proteases. This once-daily, small-molecule drug is the first orally bioavailable prophylactic treatment for HAE attacks, having successfully completed a Phase III clinical trial (meeting its primary end point) and recently receiving the U.S. Food and Drug Administration's approval for the prophylactic treatment of HAE attacks in patients 12 years and older.

PubMed: 34436898
DOI: 10.1021/acs.jmedchem.1c00511

Experimental method

X-RAY DIFFRACTION (2.097 Å)