4KTC

NS3/NS4A protease with inhibitor

Summary for 4KTC

• Entry DOI: 10.2210/pdb4ktc/pdb
• Related PRD ID: PRD_001133
• Descriptor: Serine protease NS3, NS4A peptide, ZINC ION, ... (5 entities in total)
• Functional Keywords: protease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Hepatitis C virus (isolate Japanese) (HCV); More
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein. RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26662
• Total number of polymer chains: 4
• Total formula weight: 45036.56

Authors

Zhang, H.,Ballard, J.,Vigers, G.P.A.,Brandhuber, B.J. (deposition date: 2013-05-20, release date: 2013-08-07, Last modification date: 2023-09-20)

Primary citation

Jiang, Y.,Andrews, S.W.,Condroski, K.R.,Buckman, B.,Serebryany, V.,Wenglowsky, S.,Kennedy, A.L.,Madduru, M.R.,Wang, B.,Lyon, M.,Doherty, G.A.,Woodard, B.T.,Lemieux, C.,Do, M.G.,Zhang, H.,Ballard, J.,Vigers, G.,Brandhuber, B.J.,Stengel, P.,Josey, J.A.,Beigelman, L.,Blatt, L.,Seiwert, S.D.
Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease.
J.Med.Chem., 57:1753-1769, 2014

PubMed Abstract: HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.

PubMed: 23672640
DOI: 10.1021/jm400164c

Experimental method

X-RAY DIFFRACTION (2.3 Å)