Germs against pain: Humanized bacterial sodium channels

This article refers to:

Mutant bacterial sodium channels as models for local anesthetic block of eukaryotic proteins

Mutations in voltage-gated sodium channels (Navs) are linked to a plethora of diseases ranging from inherited pain syndromes via epilepsy, arrhythmias, and paramyotonias to sudden infant death syndrome and familiar autism.¹ Each disease involves specific Nav subtypes, stressing the intriguing chance for their treatment via subtype specific Nav drug targeting. Unfortunately, to date, blockade of specific Nav subtypes remains a challenge, due to high sequence similarities and lack of the detailed molecular understanding of the mechanism of action of known sodium channel modulators.

Local anesthetics target Navs and are successfully used in the treatment of epilepsy, cardiac arrhythmia or pain, but their side effects, which are mainly due to their lack of subtype specificity, are often dose limiting. Smith and Corry present in this journal a computer modeling approach which uses the advantages of the recently obtained crystal structure of the bacterial sodium channel NavAb.^2,3 Computer simulations save time and money and potentially also reduce the experimental use of animals. One major drawback of these in silico studies is their dependency on the data to start with—the crystal structure (or homology model, if there is none) and further assumptions such as lipid bilayer composition close to the channel, its interaction with other proteins and the orientation of the amino acids of the channel protein in the 3D environment. It is save to make these assumptions as long as the studies are validated by experimental data.

Smith and Corry use the 3D model of the bacterial sodium channel NavAb to simulate binding of local anesthetic in its pore. They predict that lidocaine and benzocaine interact with certain amino acids in the pore, but as some of the hydrophobic, pore lining residues are very different from the human Navs, they use a mutagenesis approach: Introduction of F1764 and Y1771 (of hNav1.2) in the corresponding positions in the pore of NavAb changed the affinity of the compounds and lead to simulation results that can be better compared to those from experimental data of hNav1.2. Now it is possible to predict the location of the drugs in the humanized NavAb pore, their orientation and likelihood to remain in those positions. This approach turns out to improve NavAb as surrogate model for testing of drug binding in eukaryotic and/or human Navs. Their approach likely improves rationally designed drug development by refining model and experimental conditions to better mimic human or eukaryotic Navs and thus get more reliable binding results and suggestions for new and safer drugs.

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.