Further SAR studies on novel small molecule inhibitors of the hepatitis C (HCV) NS5B polymerase

Reddy, T. Jagadeeswar; Chan, Laval; Turcotte, Nathalie; Proulx, Melanie; Pereira, Oswy Z.; Das, Sanjoy K.; Siddiqui, A. M.; Wang, Wuyi; Poisson, Carl; Yannopoulos, Constantin G.; Bilimoria, Darius; L’Heureux, Lucille; Alaoui, Hicham M.A.; Nguyen-Ba, Nghe

doi:10.1016/s0960-894x(03)00670-x

Cited by 18 publications

(10 citation statements)

References 11 publications

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“…This lead compound provided a good starting point for the optimization study [91,99]. Optimization of compound 25 by introducing nitro and cyano groups at meta position generated more potent analogues 26 and 27 with IC50 values of 0.7 and 0.8 µM respectively, and retained selectivity against human DNA polymerases α, β, and γ (IC50>50µM) [100]. …”

Section: Phenylalaninesmentioning

confidence: 99%

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Polamreddy

Vishwakarma

Gundla

2016

Int J Pharm Pharm Sci

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Hepatitis C, a chronic disease affecting the global population significantly is caused majorly by Hepatitis C virus [HCV]. Among the several druggable targets explored for Hepatitis C, the viral protein, non-structural protein 5B [NS5B] is the target of choice for researchers as it is the key enzyme in the HCV replication and its active site is conserved among all genotypes. In the recent years the landscape of Hepatitis C therapies, have evolved from Peg-Interferon [PEG-INF]/Ribavirin, to directly acting anti-virus along with PEG-INF and finally, INF free regimens with greater than 90% sustained virological response [SVR]. The launch of Sofosbuvir, a nucleotide inhibitor of NS5B marks the major paradigm in hepatitis C research. Sofosbuvir exhibits, pan-genotypic activity, low barrier to resistance, highly effective and safe. However, the high prices of these medications limit their universal access. This review will focus on progress towards the discovery and development of NS5B inhibitors targeting allosteric sites and active site, covering the chemical class and structure-activity relationships.

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Section: Phenylalaninesmentioning

confidence: 99%

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Polamreddy

Vishwakarma

Gundla

2016

Int J Pharm Pharm Sci

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“…The phenyl substituents were investigated, leading to a large number of less active compounds, except for 94d , which was slightly more active (IC 50 = 2700 nM). Modification or removal of the carbonyl group caused total loss of activity . According to X‐ray structure of a complex between a derivative and RdRp (PDB id: 1NHU), the key dichlorophenyl group is buried in subpocket C and the phenylalanine moiety is maintained in the surface subpocket A .…”

Section: Thumb Pocket II Inhibitorsmentioning

confidence: 99%

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

et al. 2012

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Hepatitis C is a viral liver infection considered as the major cause of cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C virus (HCV) possesses a single positive strand RNA genome encoding a polyprotein composed of approximatively 3000 amino acids. The polyprotein is cleaved at multiple sites by cellular and viral proteases to liberate structural and nonstructural (NS) proteins. NS5B, the RNA-dependent RNA polymerase (RdRp), which catalyzes the HCV RNA replication has emerged as an attractive target for the development of specifically targeted antiviral therapy for HCV (DAA, for direct-acting antivirals). In the last 10 years, a growing number of non-nucleoside compounds have been reported as RdRp inhibitors and few are undergoing clinical trials. Over the past 5 years, several reviews were published all describing potentially active molecules. To the best of our knowledge, only one review covers the structure-activity relationships.(1) In this review, we will discuss the reported non-nucleoside molecules acting as RdRp inhibitors according to their chemical class especially focusing on structure-activity relationship aspects among each class of compounds. Thereafter, we will attempt to address the global structural requirements needed for the design of specific inhibitors of RdRp.

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“…Further optimization around the N-benzylic portion of the phenylalanine derivative led to the discovery of additional potent analogues (e.g., compounds 26, IC 50 = 1.7 μM and 27, IC 50 = 0.7 μM) ( Fig. 10) [43,44]. Structure determination of the NS5B-bound compound 26 by X-ray crystallography revealed a series of hydrogen bonding, hydrophobic, and van der Waals interactions within a shallow allosteric binding pocket in the thumb region of NS5B, about 30 Å from the catalytic site, and about 10 Å from a recently identified rGTP binding pocket (PDB ID: 1NHU) (Fig.…”

Section: Thieno[32-b]pyrrolesmentioning

confidence: 99%

Multiple Allosteric Pockets of HCV NS5B Polymerase and its Inhibitors: A Structure Based Insight

Talele

2008

CBC

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Infections caused by hepatitis C virus (HCV) are a significant worldwide health problem for which novel therapies are urgently needed. One attractive and viable therapeutic target is HCV NS5B RNA-dependent RNA polymerase (RdRp) since it is essential for the replication of the viral genome of HCV. The hunt for nonnucleoside inhibitors (NNIs) of HCV NS5B polymerase has led to the identification of several allosteric pockets. However, because the topographical features of these binding sites vary across and even within diverse HCV genotypes, the discovery of new antiviral drugs capable of inhibiting HCV RdRp in the face of variable binding pockets becomes a challenging endeavor. This review focuses on recent accomplishments in the development of new NNIs of HCV NS5B polymerase and on their binding mechanisms to the respective allosteric pockets. Potential difficulties surrounding the discovery of future NNIs targeted to different allosteric pockets of HCV NS5B and to HCV NS5B from different genotypes are also discussed.

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Further SAR studies on novel small molecule inhibitors of the hepatitis C (HCV) NS5B polymerase

Cited by 18 publications

References 11 publications

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

A Review on Anti-HCV Agents Targeting Active Site and Allosteric Sites of Non-Structural Protein 5b [Ns5b]

Structure-Activity Relationships in the Development of Allosteric Hepatitis C Virus RNA-Dependent RNA Polymerase Inhibitors: Ten Years of Research

Multiple Allosteric Pockets of HCV NS5B Polymerase and its Inhibitors: A Structure Based Insight

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