HepC NS5b Inhibitors

Chemical inhibitors of HepC NS5b include a variety of compounds that target the RNA-dependent RNA polymerase function essential for the viral replication of Hepatitis C virus. Sofosbuvir is a nucleotide analog that once incorporated into the viral RNA, results in premature termination of the polymerization process. Dasabuvir operates by binding to the palm domain of HepC NS5b, a critical region for the catalytic activity of the polymerase, thus hindering the RNA chain elongation. Similarly, Setrobuvir impedes the RNA synthesis by attaching to the thumb domain, which is necessary for the spatial arrangement of the RNA template and nucleotides. Beclabuvir also targets the thumb domain, but it does so allosterically, changing the shape of the HepC NS5b polymerase in a way that prevents the RNA synthesis.

Continuing with the mechanism of inhibition, Filibuvir attaches to the thumb domain II of HepC NS5b, which leads to a conformational shift that disrupts the polymerase's RNA synthesizing abilities. Balapiravir, through its metabolized active form, competes with natural substrates of the enzyme, causing the termination of the RNA replication. Tegobuvir and GS-9669 both bind to the thumb domain but through different mechanisms, with Tegobuvir inducing a conformational change and GS-9669 reducing the RNA synthesis by targeting the thumb site II. IDX184 and ALS-2200, both nucleotide analogs, get incorporated into the viral RNA and lead to chain termination, effectively ceasing the replication process. BMS-986094, a nucleotide prodrug, also results in premature RNA transcription termination once it is metabolized into its active form. Lastly, Deleobuvir binds to the thumb domain of HepC NS5b, inhibiting the essential RNA replication mechanism of the polymerase. Each of these chemicals disrupts the RNA-dependent RNA polymerase activity of HepC NS5b through direct interaction with the enzyme, preventing the Hepatitis C virus from replicating its RNA genome.