Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor

Autor: Jean-Laurent Paparin, Thierry Convard, Catherine Caillet, Stéphanie Bot, Dominique Louis Nestor Ghislain Surleraux, Claire Pierra, Valeria Mascia, Maria Seifer, Jean-François Griffon, Efisio Sais, Agnès Amador, David Dukhan, Cyril B. Dousson, Elodie Rosinosky, Loredana Onidi, Anna Giulia Loi, Rachid Rahali, Eric Badaroux, Massimiliano LaColla, Frédéric Leroy, David Standring, Michel Liuzzi, Joe McCarville, Julien Milhau, Ludovic Griffe, Daniel Da Costa
Rok vydání: 2016
Předmět:
0301 basic medicine
viruses
Clinical Biochemistry
Pharmaceutical Science
Hepacivirus
Viral Nonstructural Proteins
medicine.disease_cause
Crystallography
X-Ray
Virus Replication
01 natural sciences
Biochemistry
chemistry.chemical_compound
Mice
RNA polymerase
Drug Discovery
Sulfonamides
Sulfonamide (medicine)
virus diseases
Hepatitis C
Haplorhini
Molecular Medicine
medicine.drug
Binding domain
Half-Life
Genotype
Lactams
Hepatitis C virus
Allosteric regulation
Molecular Dynamics Simulation
Antiviral Agents
03 medical and health sciences
Structure-Activity Relationship
Organophosphorus Compounds
Allosteric Regulation
medicine
Animals
Humans
Molecular Biology
NS5B
Binding Sites
010405 organic chemistry
Organic Chemistry
medicine.disease
Virology
digestive system diseases
0104 chemical sciences
Protein Structure
Tertiary
Rats
030104 developmental biology
Viral replication
chemistry
Zdroj: Bioorganicmedicinal chemistry letters. 27(11)
ISSN: 1464-3405
Popis: Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.
Databáze: OpenAIRE
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