Synthetic organic chemists, molecular modelers and X-ray crystallographers fire up your engines. A great target is available, discovered by the humble centipede of all things.
Several times during my career as a neurologist, a new drug was ballyhoo’d as a non-addicting narcotic — Talwin springs to mind, among others. The hope was that a molecule with both agonist and antagonist properties wouldn’t be addicting. All basically inhibited neurotransmitter release (like the opiates), to which the synapse responded by making more receptors for the neurotransmitter, explaining tolerance, addiction to the new drug and why junkies can take doses of morphine that would kill you and I.
Have a look at Proc. Natl. Acad. Sci. vol. 110 pp. 17534 – 17539 ’13. Here’s some background. To conduct a nerve impulse, neurons have to let sodium ions flow through their membranes. This is done through proteins called sodium channels. We have 9 distinct genes for them, and most neurons express more than one.
Consider the humble pufferfish. It sometimes makes a beautiful organic molecule called tetrodotoxin (http://en.wikipedia.org/wiki/Tetrodotoxin) which blocks all but 2 of our sodium channels stopping them from conducing sodium ions. It can kill you and is 100x more potent than cyanide. Even so, it’s a very pretty molecule (to an organic chemist) with some resemblance to adamantane.
The centipede makes a 42 amino acid protein which essentially blocks only one sodium channel (NaV1.7). It’s quite potent, doing this at a concentration of 25 nanoMolar. Clinically, it is even more potent than morphine (well, in animal models anyway)
So why get excited? Because as far as we can tell, its action is on peripheral nerve fibers, not the brain. For some reason nerve fibers carrying painful impulses (a philosophic conundrum — impulses themselves are no more painful than a fire feels hot to itself) from the periphery to the spinal cord and brain use lots NaV1.7. So addiction shouldn’t be a problem.
There were some clues already — there is a disorder called congenital insensitivity to pain [Nature vol. 444 pp. 831 – 832 ’06], due to loss of function mutations in NaV1.7. Other mutations here cause several painful syndromes — erythromelalgia [J. Med. Genet. vol. 41 pp. 171 – 174 ’04 ], chronic rectal pain. These mutations cause a hyper functioning sodium channel which stays open too much.
Total absence of pain isn’t good, as we need it to warn us that we’re stressing our joints excessively. In the bad old days when there was a lot of syphilis around, it sometimes caused peripheral nerve degeneration, resulting in something called Charcot joints — http://en.wikipedia.org/wiki/Neuropathic_arthropathy.
So get cracking guys, if tetrodotoxin, a small compact molecule can nonspecifically block most sodium channels, surely you should be able to find something smaller a 42 amino acid protein to block NaV1.7 (selectively of course). I’m not sure that we have a structure of NaV1.7, but others are known, along with all their amino acid sequences, so it should be possible to model binding sites by analogy.