So last time we (rather hastily) established what excision is and what TAMs do.
So in this paper (Meyer et al. 2006) instead of chainterminating the DNA chain with a regular chain-terminator, they used a dinucleoside tetraphosphate. This compound basically consists of two nucleotides (which could be chain-terminators) and 4 phospahtes in between them. Or, if you look at it in a more relevant way, these compounds basically represent the intermediate product that is formed at the instant of excision. So imagine if you had a ddTMP as the chain-terminator sitting at the 3' terminus of the primer, and ATP came in as a PPi donor, then as ATP donates its two phosphates, the intermediate product there would be AppppddC. And of course immediately after that, we have the release of the ddC (in the form of ddCTP) and AMP (the old ATP which has now lost two phosphates).
Ok so now that we have established what the dinucleoside tetraphosphate is, we can ask what would be the advantage of its use? Basically, they show that this compound can pretty much inhibit DNA synthesis by RT as well as a regular chain-terminator. More importantly, they show that this compound binds TAMs RT better than WT RT. Mechanistically, this is relevant because it supports the model in which TAMs promotes the binding of the incoming PPi donor better as compared to WT (WildType) RT.
But what makes this compound clinically relevant is the fact that they can selectively bind a group of mutants better than WT. So hypothetically, let's say you administer AZT to a patient. That selects for TAMs which are AZT resistant. Well you can then administer NppppddNs which inihibits what you just selected for! So the two families of drugs can work synergistically in that regard.
One problem however is delivery. How is it going to get into the cell? The paper addresses this point in their discussion.
But I am getting tired of this stuff now.
The paper also discusses how they synthesize the compounds and the mechanism of ddNMP transfer to the DNA chain.
Man, i just got very impatient with this stuff all of a sudden. Next time i'll try to write more consisely with a clear structure rather than a rant. That way i'll make my point without getting bored.
ok back to the lab now.
