Hepatitis C Virus
The Hepatitis C virus (HCV) is a blood-borne, single stranded RNA virus. [2] The genome of HCV encodes a polyprotein precursor of approximatley 3,000 amino acids, which are cleaved into 1 proteins by various proteases, one of which is the NS3 serine protease. [3]
Structure of Victrelis
The active ingredient in Victrelis, boceprevir, is an equal mixture of two diastereomers made of entirely organic molecules. The molecular formula is C27H45N5O5, and the molecular weight is 519.8 grams/mole. The structural formula is as follows:[4]
Mechanism of Action
Victrelis is a protease inhibitor. A protease is an enzyme that cleaves large polypeptides to create fragments that are small enough to be sequenced for effective replication[5] Victrelis specifically inhibits the HCV NS3/4A protease, which is responsible for cleavage at four different sites along the polyprotein: NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B.[6] The active ingredient in Victrelis, boceprevir, covalently binds to the active site serine (Ser139) in the NS3 protease. The nucleophilic oxygen in the hydroxyl of the Ser139 group binds to the ???.[7] When unbound, Ser139 forms hydrogen interactions with His157 and Asp99 to create a catalytic triad.[8] In previous experiements, when any member of the catalytic triat was replaced by a different residue, cleavage at the NS3/NS4A, NS4A/NS4B, NS4B/NS5A, and NS5A/NS5B locations was inhibited.[9] By inhibiting the protease from cleaving the HCV at the NS3/NS4A location, the polyprotein is unable to be cleaved into smaller, functional proteins that compose replication machinery of HCV, thereby inhibiting viral replication.[10]
Mammals also utilize serine proteases to cleave lengthy polypeptides.[11] Bocepreivir was tested among several different mammalian proteases, including those that are vital for blood clotting, digestion, and antibody neutralization, and it was found to be exclusively selective for inhibition of the NS3 serine protease of HCV only.[12]
Structure When Bound to NS3 Serine Protease
How Victrelis Induces Change
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