In a study, researchers have identified two drugs simeprevir, and grazoprevir that synergize with the viral polymerase inhibitor remdesivir to inhibit virus replication, increasing antiviral activity as much as 10-fold. SARS-CoV-2 contains a single, large positive-sense single-stranded RNA as the genetic material, which is directly translated by host cell ribosomes. The 16 non-structural proteins are processed by two virus-encoded cysteine proteases, the papain-like protease (PLpro) and a 3C-like protease (3CLpro 6), also referred to as the main protease (Mpro).
These two proteases are essential for the virus life cycle and are involved in the production of a functional viral RNA polymerase. Due to the similar structure of SARS-CoV-2 Mpro and the HCV protease, the researchers initiated a search for the drug candidate among the available HCV protease inhibitor drugs. Then such HCV protease inhibitors were identified. These inhibitors docked snuggly into the substrate-binding cleft of Mpro.
The researchers found that the inhibitory effects were additive or synergistic depending on the HCV drug used to inhibit virus replication in vitro. They report that boceprevir and vaniprevir (which strongly inhibits the protease) act additively with remdesivir to inhibit virus replication, whereas simeprevir and grazoprevir, (which moderately/strongly inhibits) act synergistically with remdesivir.
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