Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors

Belema, Makonen; López, Omar D.; Bender, John A.; Romine, J.; Laurent, Denis R. St.; Langley, David R.; Lemm, Julie A.; O’Boyle, Donald R.; Sun, Jin-Hua; Wang, Chunfu; Fridell, Robert A.; Meanwell, Nicholas A.

doi:10.1021/jm401793m

Cited by 71 publications

(58 citation statements)

References 218 publications

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“…Initial binding studies with fragmented small monomeric inhibitors demonstrated that binding appears to be necessary but not sufficient for inhibition, and the authors postulated an additional function to transmit the inhibitory potential of the compounds (52). The different potencies of the NS5A inhibitors might reflect their different potentials for inducing this conformational change.…”

Section: Discussionmentioning

confidence: 99%

NS5A Inhibitors Impair NS5A–Phosphatidylinositol 4-Kinase IIIα Complex Formation and Cause a Decrease of Phosphatidylinositol 4-Phosphate and Cholesterol Levels in Hepatitis C Virus-Associated Membranes

Reghellin

Donnici

Fenu

et al. 2014

Antimicrob Agents Chemother

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bThe hepatitis C virus (HCV) nonstructural (NS) protein 5A is a multifunctional protein that plays a central role in viral replication and assembly. Antiviral agents directly targeting NS5A are currently in clinical development. Although the elucidation of the mechanism of action (MOA) of NS5A inhibitors has been the focus of intensive research, a detailed understanding of how these agents exert their antiviral effect is still lacking. In this study, we observed that the downregulation of NS5A hyperphosphorylation is associated with the actions of NS5A inhibitors belonging to different chemotypes. NS5A is known to recruit the lipid kinase phosphatidylinositol 4-kinase III␣ (PI4KIII␣) to the HCV-induced membranous web in order to generate phosphatidylinositol 4-phosphate (PI4P) at the sites of replication. We demonstrate that treatment with NS5A inhibitors leads to an impairment in the NS5A-PI4KIII␣ complex formation that is paralleled by a significant reduction in PI4P and cholesterol levels within the endomembrane structures of HCV-replicating cells. A similar decrease in PI4P and cholesterol levels was also obtained upon treatment with a PI4KIII␣-targeting inhibitor. In addition, both the NS5A and PI4KIII␣ classes of inhibitors induced similar subcellular relocalization of the NS5A protein, causing the formation of large cytoplasmic NS5A-containing clusters previously reported to be one of the hallmarks of inhibition of the action of PI4KIII␣. Because of the similarities between the effects induced by treatment with PI4KIII␣ or NS5A inhibitors and the observation that agents targeting NS5A impair NS5A-PI4KIII␣ complex formation, we speculate that NS5A inhibitors act by interfering with the function of the NS5A-PI4KIII␣ complex.T he recent advent of direct-acting antivirals (DAAs) against hepatitis C virus (HCV) is radically transforming the treatment scenario for patients with chronic hepatitis C infection. These new drugs offer the promise of well-tolerated interferonfree oral regimens that are able to cure the majority of infected patients (1).Initially, the effort to identify DAAs focused primarily on inhibitors of two virally encoded enzymes: the nonstructural 3/4A (NS3/4A) protease and the NS5B polymerase. More recently, however, the clinical validation of NS5A inhibitors (2) has generated increasing interest in this target class. The first NS5A inhibitors were discovered by a phenotypic screen based on the genotype 1b replicon system (3, 4). The initial lead compounds had moderate potency and a narrow spectrum of anti-HCV activity, mainly on genotype 1b. Subsequent medicinal chemistry efforts (4) resulted in the design of picomolar inhibitors characterized by a peculiar and highly symmetrical dimeric structure (reviewed in reference 5). The most-studied agent of this "palindromic" NS5A inhibitor class is daclatasvir (DCV, formerly BMS-790052) (6), a highly optimized biphenyl derivative inhibitor for which regulatory approval is currently being sought.Different chemical isotypes were initially claimed to ...

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Section: Discussionmentioning

confidence: 99%

NS5A Inhibitors Impair NS5A–Phosphatidylinositol 4-Kinase IIIα Complex Formation and Cause a Decrease of Phosphatidylinositol 4-Phosphate and Cholesterol Levels in Hepatitis C Virus-Associated Membranes

Reghellin

Donnici

Fenu

et al. 2014

Antimicrob Agents Chemother

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“…Ledipasvir inhibits the NS5A replication complex which plays a critical role in viral replication, despite having no known enzymatic activity [11]. In fact, the exact mechanism of NS5A is still unknown, but its role is so essential that NS5A inhibitors have produced the fastest viral load declines of any antiviral class [12].…”

Section: Ledipasvirmentioning

confidence: 99%

Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C

Fazel

Lam

Golabi

et al. 2015

Expert Opinion on Drug Safety

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In trials enrolling more than 3000 patients, LDV/SOF is well tolerated with a good safety and side-effect profile in diverse cohorts, including previous direct-acting antiviral (DAA) treatment failures, liver transplant recipients, decompensated cirrhosis and HIV/HCV co-infection. As with all DAAs, the potential for drug-drug interactions must be carefully evaluated, as demonstrated by recent post-marketing reports of symptomatic bradycardia when LDV/SOF is co-administered with amiodarone. Currently, dose recommendations cannot be given for patients with advanced renal disease. Trials in this population are ongoing, more study is warranted. When surveying the DAA regimens available, efficacy, safety and tolerability of LDV/SOF is comparable or better, and LDV/SOF provides an option with convenient single-tablet, once daily, ribavirin-free dosing with relatively few significant drug-drug interactions.

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“…It is being developed in combination with PEG-IFN/RBV 66,67 and with other direct-acting antiviral agents including daclatasvir (an NS5A inhibitor) 47 and BMS-791325 (an NS5B polymerase inhibitor). 68 …”

Section: Asunaprevir (Bms-650032)mentioning

confidence: 99%

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

Kazmierski

Jarvest

Plattner³

et al. 2014

Macrocycles in Drug Discovery

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Enormous progress has been made towards an all-oral, very highly sustained viral response (considered a cure) treatment of hepatitis C. Key ingredients of these therapies are hepatitis C virus (HCV) protease inhibitors (PIs). The first generation linear and covalent PIs, telaprevir and boceprevir, were discovered through the enzyme substrate-based approach and are being followed by a second generation of non-covalent PIs. Many of these are macrocycles, as exemplified by the recently FDA-approved simeprevir. This chapter will detail the science successfully employed in both the substrate-based and inhibitor macrocyclization approaches. Additionally, as HCV PI C-terminal motifs develop critical contacts with the enzyme catalytic Ser139 and adjacent sites, this chapter discusses the mechanistic and structural details of such interactions for both the reversible covalent ketoamide as well as non-covalent sulfonamide and carboxylic acid moieties. Efforts to explore a cyclic boronate motif in various linear and cyclic HCV PIs in search of both Ser139-specific and opportunistic enzyme–inhibitor interactions are also summarized herein. In addition, key clinical and marketed PIs are described, including extensive references to primary literature. Finally, this chapter briefly covers key macrocyclic inhibitors of HCV RNA-dependent RNA polymerase NS5B and selected non-HCV macrocyclic protease inhibitors in order to provide additional insights into the successful design of macrocyclic drugs.

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Discovery and Development of Hepatitis C Virus NS5A Replication Complex Inhibitors

Cited by 71 publications

References 218 publications

NS5A Inhibitors Impair NS5A–Phosphatidylinositol 4-Kinase IIIα Complex Formation and Cause a Decrease of Phosphatidylinositol 4-Phosphate and Cholesterol Levels in Hepatitis C Virus-Associated Membranes

NS5A Inhibitors Impair NS5A–Phosphatidylinositol 4-Kinase IIIα Complex Formation and Cause a Decrease of Phosphatidylinositol 4-Phosphate and Cholesterol Levels in Hepatitis C Virus-Associated Membranes

Safety analysis of sofosbuvir and ledipasvir for treating hepatitis C

Linear and Macrocyclic Hepatitis C Virus Protease Inhibitors: Inhibitor Design and Macrocyclization Strategies for HCV Protease and Related Targets

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