[johnny123]

HIV Reverse Transcriptase unblocking its template primer when blocked by drugs like AZT using ATP/ADP/AMP phosphorylation. What kinds of organic molecules resist phosphorylation or are less likely to receive the ATP?

[johnny123]

I was told Alkane groups resist phosphorylation but I'm having difficulty proving this statement with google. Could someone help out?

[Yggdrasil]

One potential problem with this approach is that nucleoside inhibitors like AZT first need to be phosphorylated by cellular kinases.  Only after they have been converted to a triphosphate form can they be incorporated into viral DNA by reverse transcriptase.  Therefore modifying the drug to resist phosphorylation would be likely to render the drug inactive.

An alternative strategy would be to design a nucleotide analog that, once incorporated into DNA, cannot be removed by pyrophosphoroylsis.  To the best of my knowledge, such compounds have not been described yet.

Another interesting idea is to design chain terminators that do not block polymerization right after they are added, but rather block polymerase activity only after a few additional nucleotides have been added to the inhibitor.  Such delayed chain terminator drugs may make it difficult for the enzyme to remove them via pyrophosphorolysis.