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Description
The life-threatening virus, Hepatitis C (HCV), creates problems in the health of millions of people worldwide and is a leading cause of liver cancer. Previous treatments to clear the virus have included a dual or regimen of interferon ribavirin as well as the availability of new antiviral drugs. Unfortunately, current treatments are associated with serious side effects and only effective in select genotypes. A new therapeutic treatment was recently approved by the FDA and shows promise in being a curable solution. However, with the reality that viruses continually mutate, creation of a library of compounds shown to inhibit the virus is vital. The Bergdahl group has recently published a novel total synthesis of a class of benzimidazole compounds, which has shown to prevent replication of the virus in a unique way by binding to the conserved internal ribosome entry site (IRES) of the HCV RNA preventing initiation of translation. The route was structured for a late introduction of diversity to allow for ease in synthesis of diverse derivatives. In addition, an X-ray crystal structure of the bound inhibitor-RNA complex has been achieved. The crystal structure allows for guided structural modifications of analog compounds to improve binding affinity to the IRES and consequently drug effectiveness. Once tested, the recently gained bioassay and Förster resonance energy transfer (FRET) has continuously directed the diversity introduced in the compounds. Currently, around 20 analogs have been synthesized in the Bergdahl group and have shown excellent activity (EC₅₀ = 3-90 µM)) against the virus. Many structure-binding relationships of alkylamino-substituted benzimidazole ligands were established. The inhibitors have provided valuable data towards the synthesis of additional compounds in anticipation of more powerful molecules for the treatment of HCV. Future derivatives are expected to act more efficiently due to more drastic changes to the backbone of the structure without compromising the toxicity to the human body. The data-driven approach allows for continuation of optimization of binding affinity. This will also allow selectivity in the syntheses of drugs with the hope of having readily available and cost effective treatments for the HCV virus.
