The Discovery and Development of Daclatasvir: An Inhibitor of the Hepatitis C Virus NS5A Replication Complex

Abstract

The discovery of the hepatitis C virus (HCV) NS5A replication inhibitor daclatasvir (1) had its origins in a phenotypic screening lead. However, during the optimization campaign, it was observed that some members of the chemotype underwent a radical dimerization under the assay conditions. This redirected the effort to focus on palindromic molecules, a species subsequently shown to complement the dimeric nature of the NS5A protein. The most challenging aspect of the discovery program was extending antiviral activity to encompass GT-1a virus which was accomplished only after the development of extensive structure-activity relationships. In clinical trials, oral administration of daclatasvir (1) produced a profound effect on viral load with onset that was more rapid than had been seen previously with either NS3 protease or NS5B polymerase inhibitors. 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.

Modeling hepatitis C virus kinetics during liver transplantation reveals the role of the liver in virus clearance

“…To determine the effect of Huh7 hepatoma cells on HCV clearance in vitro, we measured the half-life of HCV virions at 37°C in cell culture medium in the absence and presence of chronically infected Huh7 cells by monitoring the decrease of HCV RNA over time ( Figure 4 ). To measure HCV half-life in cell culture medium in the presence of chronically HCV-infected cells, we established a steady-state chronic infection in Huh7 cells, and then inhibited the secretion of HCV from the cells using 1 nM of the NS5a inhibitor daclatasvir to block HCV replication and secretion ( Meanwell and Belema, 2019 ) or 200 µM naringenin to block HCV secretion ( Goldwasser et al, 2011 ). In the absence of cells, the HCV half-life observed was 112 hr ( Figure 4a ).…”

A fruitful century for the scalable synthesis and reactions of biphenyl derivatives: applications and biological aspects

“…Due to the presence of substituted biphenyl increases the polarity of the heterocyclic skeleton which might be the reason for high antitubercular (anti-TB) activities via interacting with the MurB inhibitors 186 Treatment of heart failure with a combination of valsartan Neprilysin inhibitor 186,187 Antihypertensive Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inammation associated with hypertension, we evaluated the anti-inammatory potential and the underlying mechanism of masartan 188 Anti-inammatory 188 Antiviral As a result of sp 2 hybridization of CNTs between the drug and target protein sequence, leads to improving the uorescence reactivity. Because the conjugated system of biphenyl and the presence of Cs/CNT can increase the electroactive surface area of the electrode, leading to an increase in the number of structural aws 189 Treatment selections for hepatitis C virus 189,190 Active for the AT1 receptor [191][192][193] Lung-selective muscarinic cholinergic receptor (mAChR) antagonist…”

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

“…Successful drug, daclatasvir 3) was approved in 2014 by the European Medicine Agency and in 2016 by the FDA, under the brand name Daklinza. It is usually coadministered with sofosbuvir [158]. It was proposed that daclatasvir blocks the transport of viral RNAs to the assembly sites and thus inhibits viral particle assembly [159].…”