Scratching away at pain ?


We’ve all felt pain. And although we have different thresholds and differing definitions of what pain is we commonly all have one thing in common – we don’t like it. Although there are a variety of analgesics available to us they have their limitations with respect to either efficacy (they don’t manage the pain very well) or they have unwanted side effects (CNS disturbances, addiction potential etc).

Although well acknowledged within the drug discovery community that there is an acute need for novel pain therapeutics, particularly for chronic neuropathic pain, the lack of clinical translatability of preclinical pain models has led many large companies to exit or avoid this area. It is perhaps this historical backdrop that makes the NaV1.7 (SCN9A) story so interesting. The role of voltage-gated sodium channels (NaVs) in generating the upstroke of action potentials, and hence controlling excitability in nerves, has been pharmacologically exploited for decades with local anaesthetics. Most of us have experienced them first hand on a trip to the dentist with a pain numbing lidocaine injection. If you have, then you’ve also experienced some of the downsides of a non-specific NaV blocker, in this case loss of sensation. Knowing which of the 9 NaV family members (NaV1.1 – NaV1.9) to target to deliver effective analgesia whilst not impacting on other important NaV channel mediated functions was a conundrum for many years. This changed in the mid-2000s when genetic studies looking at patients with recurrent pain (primary erythermalgia, paroxysmal extreme pain disorder) and those with an inability to sense pain (congenital insensitivity to pain) identified the SCN9A gene, which encodes the NaV1.7 channel, as the culprit. With both loss and gain of function mutations in humans giving opposing phenotypes, constituting arguably the highest level of pre-clinical target validation, considerable attention turned to this channel and developing selective blockers. It has not however been a straight forward journey and ten years down the line there are blockers entering early clinical development, albeit with varying degrees of success and varying selectivity profiles (see table below). And it is the latter, selectivity, that has provided the considerable challenge from a drug discovery perspective – the degree of conservancy between the 9 family members is extremely high, particularly in the pore region of the channels where most sodium channel blockers bind.

Nav1.7

From Martz, L. SciBX 7(23); doi:10.1038/scibx.2014.662 (2014)

 

Peptide toxins which profoundly affect the gating (activation and/or inactivation) of NaV channels have attracted attention as they can demonstrate isoform selectivity. These target the voltage sensing domains (VSDs) of the NaV channels, an area which not surprisingly based upon the differing activation and inactivation profiles exhibited by the NaV family members has the highest sequence divergence. In 2013 a low molecular weight compound, PF-04856264, was reported1 to display selectivity for NaV1.7 over other isoforms. PF-04856264 was also reported to bind to the 4th VSD domain (VSD4), the conclusion based upon a series of comprehensive functional studies using chimeric channels. In a recent paper published by investigators from Genentech and Xenon (Ahuja et al2) the binding of this class of compounds (aryl sulphonamides) to VSD4 has not only been confirmed buts its structural basis for isoform selectivity explained. The group describe an elegant strategy of generating crystal structures of a chimeric human/bacterial channel to overcome the challenge of expressing full length NaV1.7. The chimera retained the key pharmacological properties of the channel and importantly produced high levels of protein to facilitate the crystallographic studies. The structural information outlined in the paper is consistent with the aryl sulphonamides binding to VSD4 and stabilising it in an activate state. Furthermore mutational analysis of the VSD4 receptor site identified the key motifs required for aryl sulphonamide binding and identified the key structural motifs that are responsible for the isoform selectivity of this class of compounds.drug binding site

From Ahuja et al 2015

At the Sussex Drug Discovery Centre we are big fans of structurally enabled targets and anticipate that the structural information determined by Ahuja et al will make a pivotal contribution to the design of improved NaV blockers for pain. However in common with many other drug discovery stories the path from target identification to delivery of a drug can be long and irritating………….. interestingly NaV1.7 is also implicated in itch3.

References:

  1. McCormack et al (2013) Voltage sensor interaction site for selective small molecule inhibitors of voltage gated sodium channels. PNAS; www.pnas.org/cgi/doi/10.1073/pnas.1220844110
  2. Ahuja et al (2015) Strcutral basis of NaV1.7 inhibition by an isoform-selective small molecule antagonist. Science 350(6267), 5464-1 – 5464-8
  3. Devigili et al (2014) Paroxysmal itch caused by a gain-of-function NaV1.7 mutation. Pain 155(9), 1702 – 1707

Blog written by Martin Gosling

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