How many more metabolites like this are out there?

3′ deoxy 3′ 4′ didehydro cytidine triphosphate — doesn’t roll’ tripgingly on the tongue’ does it? (Hamlet Act 3, scene 2, 1–4).  Can you draw the structure?  It is the product of another euphoniously named enzyme — Viperin.  Abbreviated ddhCTP it is just cytidine triphosphate with a double bond between carbons 3 and 4 of the sugar.

Viperin is an enzyme induced by interferon which inhibits the replication of a variety of viruses. [ Nature vol. 558 pp. 610 – 614 ’18 ] describes a  beautiful sequence  of reactions for ddhCTP’s formation using S-Adenosyl Methionine (SAM).  ddhCTP acts as a chain terminator for the RNA dependent RNA polymerases of multiple members of Flaviviruses (including Zika).

However the paper totally blows it for not making the point that ddhCTP is extremely close to a drug (which has been used against AIDS for years — Zalcitabine (Hivid) — http://www.molbase.com/en/name-Zalcitibine.html which is just ddC.  ddhCTP is almost the same as ddC — except that there is no triphosphate on the 5′ hydroxyl (which enzymes in the body add), and instead of a double bond between carbons 3 and 4 of the sugar, both carbons are fully reduced (CH2 and CH2).  So ddhCTP is Nature’s own Zalcitabine.

It is worth reflecting on just how many other metabolites are out there acting as ‘natural’ drugs that we just haven’t found yet.

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Comments

  • John Wayne  On July 6, 2018 at 4:22 pm

    I’m not a fan of the mechanism they propose. I looked at the reference they provided as a precedent; I don’t think it is relevant. I think I am too young to be so grumpy about the lack of basic chemistry knowledge expressed in the literature.

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