Question

In its subcellular location, this antiviral prodrug is converted to its active form, a 5’-triphosphate analog that results in non-obligate chain termination. that is activated only in a specific cell type that is infected by the virus.

1. Identify the locations of substitutions of the active form of this drug.  
2. Propose a mechanism of how its incorporation by polymerase would result in chain termination.
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Answer 1

In this drug, uracil is being modified, so this uracil analog will try to incorporate in complement with Adenosine by viral RNA polymerase in an infected cell.

This drug undergoes several metabolic pathways to form an intermediate named as 2'-deoxy-2'-α-fluoro-β-C-methyluridine-5'-triphosphate. Inspite of having a 3'OH group which can perform the function of a nucleophile for the incoming nucleotide, the methyl group of the intermediate undergoes a steric clash with the nucleotide and does not support the formation of phospho diester bond. So there is a chain termination in RNA strand formation of the virus.