id	author	title	date	pages	extension	mime	words	sentences	flesch	summary	cache	txt
cord-017764-h1w9gbxk	Meanwell, Nicholas A.	The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex	2018-06-08		.txt	text/plain	9250	389	39	A groundbreaking clinical trial that combined daclatasvir (1) with the protease inhibitor asunaprevir (52) established that a chronic HCV infection could be cured with small molecule therapy in the absence of immune stimulation, setting the stage for approval of this regimen for the treatment of GT-1b-infected subjects by the Japanese health authorities on July 4, 2014. The discovery of the hepatitis C virus (HCV) nonstructural 5A (NS5A) replication complex inhibitor daclatasvir (1) began with the development of a genotype 1b (GT-1b) replicon that was implemented as a phenotypic screen using a design that conferred a stringent triaging of hit molecules [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] . A screen of compounds selected from the library of HCV NS5A inhibitors assessed in the presence of 1 using the Tyr93Asn GT-1aresistant replicon, followed by SAR optimization, identified Syn-395 (52) as a molecule capable of restoring the sensitivity of resistant virus to the inhibitory effects of 1. Discovery of daclatasvir, a pan-genotypic hepatitis C virus NS5A replication complex inhibitor with potent clinical effect	./cache/cord-017764-h1w9gbxk.txt	./txt/cord-017764-h1w9gbxk.txt