New small molecule inhibitors of hepatitis C virus

Wei, Wanguo; Cai, Cuifang; Kota, Smitha; Takahashi, Virginia; Feng, Na; Strosberg, A. Donny; Snyder, John K.

doi:10.1016/j.bmcl.2009.10.070

Cited by 22 publications

(40 citation statements)

References 15 publications

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“…When added in 10 to 20 μM concentrations to HCV-infected cells, these peptides reduced production of the virus, as determined both by limited dilution Tissue Culture Infectious Dose – 50% (TCID-50) studies [23] and by Real Time RT-PCR measurement of HCV RNA[69–70]. …”

Section: Inhibition Of Hcv Production By Inhibitors Of Core Dimerizationmentioning

confidence: 99%

Core as a Novel Viral Target for Hepatitis C Drugs

Strosberg

Kota

Takahashi

et al. 2010

Viruses

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Hepatitis C virus (HCV) infects over 130 million people worldwide and is a major cause of liver disease. No vaccine is available. Novel specific drugs for HCV are urgently required, since the standard-of-care treatment of pegylated interferon combined with ribavirin is poorly tolerated and cures less than half of the treated patients. Promising, effective direct-acting drugs currently in the clinic have been described for three of the ten potential HCV target proteins: NS3/NS4A protease, NS5B polymerase and NS5A, a regulatory phosphoprotein. We here present core, the viral capsid protein, as another attractive, non-enzymatic target, against which a new class of anti-HCV drugs can be raised. Core plays a major role in the virion’s formation, and interacts with several cellular proteins, some of which are involved in host defense mechanisms against the virus. This most conserved of all HCV proteins requires oligomerization to function as the organizer of viral particle assembly. Using core dimerization as the basis of transfer-of-energy screening assays, peptides and small molecules were identified which not only inhibit core-core interaction, but also block viral production in cell culture. Initial chemical optimization resulted in compounds active in single digit micromolar concentrations. Core inhibitors could be used in combination with other HCV drugs in order to provide novel treatments of Hepatitis C.

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Section: Inhibition Of Hcv Production By Inhibitors Of Core Dimerizationmentioning

confidence: 99%

Core as a Novel Viral Target for Hepatitis C Drugs

Strosberg

Kota

Takahashi

et al. 2010

Viruses

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“…SL209-biotin is a biotinlyated derivative of SL209. “*” indicates that structures of SL201, SL209, and SL231 have been previously published in Wei et al 2009 [24], Strosberg et al 2010 [15], and Ni et al 2011 [23]. B: Levels of inhibition.…”

Section: Resultsmentioning

confidence: 72%

“…The compounds were analyzed in the core dimerization AlphaScreen assay to determine the IC 50 values, on naïve Huh-7.5 cells to calculate the CC 50 values and finally on HCV infected (Multiplicity Of Infection – MOI – 5 to 8) Huh-7.5 cells to determine the EC 50 values using Real Time RT-PCR.“*”indicates previously published in Wei et al [24], Strosberg et al [15], Mousseau et al [17], Ni et al [23].…”

Section: Resultsmentioning

confidence: 99%

Direct Binding of a Hepatitis C Virus Inhibitor to the Viral Capsid Protein

et al. 2012

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Over 130 million people are infected chronically with hepatitis C virus (HCV), which, together with HBV, is the leading cause of liver disease. Novel small molecule inhibitors of Hepatitis C virus (HCV) are needed to complement or replace current treatments based on pegylated interferon and ribavirin, which are only partially successful and plagued with side-effects. Assembly of the virion is initiated by the oligomerization of core, the capsid protein, followed by the interaction with NS5A and other HCV proteins. By screening for inhibitors of core dimerization, we previously discovered peptides and drug-like compounds that disrupt interactions between core and other HCV proteins, NS3 and NS5A, and block HCV production. Here we report that a biotinylated derivative of SL209, a prototype small molecule inhibitor of core dimerization (IC50 of 2.80 µM) that inhibits HCV production with an EC50 of 3.20 µM, is capable of penetrating HCV-infected cells and tracking with core. Interaction between the inhibitors, core and other viral proteins was demonstrated by SL209–mediated affinity-isolation of HCV proteins from lysates of infected cells, or of the corresponding recombinant HCV proteins. SL209-like inhibitors of HCV core may form the basis of novel treatments of Hepatitis C in combination with other target-specific HCV drugs such as inhibitors of the NS3 protease, the NS5B polymerase, or the NS5A regulatory protein. More generally, our work supports the hypothesis that inhibitors of viral capsid formation might constitute a new class of potent antiviral agents, as was recently also shown for HIV capsid inhibitors.

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“…In situ acylation [lowering the triazine lowest unoccupied molecular orbital (LUMO)] and thermolysis promoted cycloaddition with loss of nitrogen to afford the protected indoline alkaloid scaffold 10 which could be readily deprotected to scaffold 11. A library of 199 related indoline alkaloids derived from scaffold 12-14 were synthesized via N14 diversification employing acyl and sulfonyl chlorides (19).…”

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confidence: 99%

Discovery of new antimalarial chemotypes through chemical methodology and library development

Brown

Cheng

Wei

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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In an effort to expand the stereochemical and structural complexity of chemical libraries used in drug discovery, the Center for Chemical Methodology and Library Development at Boston University has established an infrastructure to translate methodologies accessing diverse chemotypes into arrayed libraries for biological evaluation. In a collaborative effort, the NIH Chemical Genomics Center determined IC 50 's for Plasmodium falciparum viability for each of 2,070 members of the CMLD-BU compound collection using quantitative high-throughput screening across five parasite lines of distinct geographic origin. Three compound classes displaying either differential or comprehensive antimalarial activity across the lines were identified, and the nascent structure activity relationships (SAR) from this experiment used to initiate optimization of these chemotypes for further development.T he synthesis of compound libraries embodying structural diversity and complexity is one potential avenue to enabling the discovery of potent and selective bioactive agents (1-3). Synthetic methodology aimed at library design and distribution is the focus of the Center for Chemical Methodology and Library Development at Boston University (CMLD-BU). Currently the CMLD-BU maintains a collection of approximately 2,500 compounds derived from reaction methodologies developed in the Center and associated groups. The CMLD-BU has developed a workflow that leverages focused methodology development (4) and identification of new scaffolds and chemical reactions utilizing multidimensional reaction screening (5) for the synthesis of libraries.In a collaboration between the CMLD-BU and the NIH Chemical Genomics Center (NCGC), an effort to discover unique chemotypes which inhibit the viability of P. falciparum, the causative agent of malaria, is underway. Malaria not only inflicts tremendous suffering and morbidity on the human population, but has dramatically influenced the course of civilization with profound sociological and economic implications (6). In response, there have been significant screening efforts for new antimalarial agents (7,8). Effective treatments continue to be needed in part due to acquired resistance of P. falciparum. Identification of molecular targets affecting the viability of malaria is necessary for efficient drug development as is the discovery of chemotypes active across a variety of geographic isolates. With an aim to improve the process of identifying new compounds and targets, we have used quantitative high-throughput screening (qHTS) to achieve pharmacological fingerprints of chemical libraries (9). This technique tests each compound as a seven point titration covering four orders of magnitude in concentration thus allowing sufficient resolving power by virtue of IC 50 determinations to reveal subtle differences in compound activities between parasite lines. A compound with a differential chemical phenotype (DCP) can enable mapping of target genes using genetic recombination wherein the DCP emerges between two or more...

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New small molecule inhibitors of hepatitis C virus

Cited by 22 publications

References 15 publications

Core as a Novel Viral Target for Hepatitis C Drugs

Core as a Novel Viral Target for Hepatitis C Drugs

Direct Binding of a Hepatitis C Virus Inhibitor to the Viral Capsid Protein

Discovery of new antimalarial chemotypes through chemical methodology and library development

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