Novel Inhibitors of the Hepatitis C Virus

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Talley_umbc_0434D_11435.pdf (3.07 MB)

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http://hdl.handle.net/11603/15102

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UMBC Theses and Dissertations

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Author/Creator ORCID

Date

2016-01-01

Type of Work

dissertations
Text

Department

Chemistry & Biochemistry

Program

Chemistry

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This item may be protected under Title 17 of the U.S. Copyright Law. It is made available by UMBC for non-commercial research and education. For permission to publish or reproduce, please see http://aok.lib.umbc.edu/specoll/repro.php or contact Special Collections at speccoll(at)umbc.edu
Distribution Rights granted to UMBC by the author.

Subjects

Hepatitis C
Medicinal Chemistry
Photoaffinity Label
Zinc Binding

Abstract

Several analogs of the natural product UK-1 have been identified as potent inhibitors of hepatitis C virus (HCV) replication in a replicon assay. One set of inhibitors has been shown to inhibit the HCV non-structural protein 3 helicase (NS3h), while another acts via an unknown cellular target. Efforts have been focused on (1) identifying the inhibitor binding pocket within the NS3 helicase and (2) exploring the possible role zinc binding may play in the inhibitory mode of action of the latter. Lead HCV replication inhibitors, inactive against NS3h, have been shown to bind zinc. Within the HCV genome, at least three non-structural proteins (NS2, NS3, and NS5A) contain/require a structural zinc ion and all three proteins are required for viral replication. Disruption of zinc binding within any of the three proteins severely hinders or eliminates protein function, thus inhibiting viral proliferation. It is therefore hypothesized that the activity of lead compounds is related to the coordination of one or more protein-bound structural zinc ions, causing a perturbation of protein structure that diminishes protein activity and thereby inhibits viral replication. To investigate whether or not zinc binding plays a role in the activity of lead HCV replication inhibitors, a series of analogs have been synthesized with structural modifications expected to increase zinc affinity. In addition, a structure activity relationship (SAR) study was performed to explore the effects of hydrogen bonding and sterics/hydrophobicity on inhibitor efficacy. Lead modification has led to a potent inhibitor of HCV replication (EC₅₀= 0.6 µM) that shows minimal toxicity to host-cells (SI> 160). The SAR study, syntheses, zinc binding experiments, and biological data will be presented. Two lead compounds inhibit HCV NS3 helicase activity with low to sub-micromolar EC₅₀ values. Identification of the binding pocket within NS3h would allow for structure-based drug design, facilitating the development of increasingly potent inhibitors. As such, a photoactivatable analog of a lead helicase inhibitor has been designed to be used in a photoaffinity labeling experiment; this analog has been shown to be similarly effective against the NS3 helicase. The design, syntheses, photolysis data, and results of NS3h photolabeling experiments will be presented herein.