We have just published a paper (accepted today, see attached PDF) showing that a therapeutically relevant enzyme inhibitor binds almost exclusively to a covalent intermediate on the catalytic pathway. I believe that drug-design people are usually thinking about "hitting" either the free enzyme, or some type of an enzyme--substrate complex, with an inhibitor acting as a potential therapeutic agent. This is why I could not find almost any other examples similar to our work. My question is this:
Does anyone know about published work showing other examples of high-potency, therapeutically relevant enzyme inhibitors, binding preferentially or even exclusively to covalent intermediates? I would be very grateful for relevant literature references.
Incidentally, if the inhibitor binds in this way, the upshot is that "static" structural studies (X-Ray, solution NMR), "static" binding studies (ITC) or even "dynamic" biophysical studies (SPR on/off) don't work. The only experimental method that works is the biochemical (kinetic) assay: We have to have the enzyme pass through the entire catalytic cycle, in order for the inhibitory effect to manifest itself.
Thanks in advance...
The fluoroquinolone antibacterial drugs (e.g. ciprofloxacin) are inhibitors of type II topoisomerases (gyrase and topoIV). They bind to the covalent enzyme-DNA complex, an intermediate in the catalytic cycle in which the DNA backbone is broken in two places. The end result is double-stranded breakage of the DNA. Such inhibitors are referred to as topoisomerase poisons.
IMPDH/MPA and gyrase/cipro are the only examples I've come across that come to mind. Gyrase kinetics are tough to measure - my colleague Tony Maxwell is a leader in this. IMPDH papers you may know already include JBC (1993) 268:27286, Cell (1996) 85;921, Biochem Pharmacol (1999) 58:867.
Celgene Avilomics is working on inhibitors that form covalent bonds with the enzyme target. One of these programs was a "highly-selective Bruton’s Tyrosine Kinase (Btk) inhibitor" that was acquired by Celgene's acquisition of Avila Therapeutics.
http://www.avilatx.com
http://www.xconomy.com/boston/2012/01/26/celgene-buys-avila-for-350m-gaining-promising-covalent-drugs/
http://www.celgene.com/research-development/rd-locations/avilomics-research/
Thank you, Stephen and Adam, for your very helpful answers. I did have a sense that "hitting" a covalent intermediate on the enzyme's reaction pathway is fairly unique occurrence in drug design. Based on your answers, it seems that cipro/gyrase is really the only practically operational system out there, is that correct? If so, than the A110/IMPDH combo (aside from weakly bound mycophenolic acid/IMPDH) would end up being the only other documented case, yes?
Mark, I appreciate your taking the time to post as well, but I think you might have slightly misunderstood my question. My question was not regarding covalent (irreversible) inhibitors of enzymes, but rather any kind of inhibitors (either covalent or not) that bind to a covalent intermediates on the enzyme catalytic pathway.
Thanks again...
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