This, however, is not necessarily straight-forward because many cell lines with confirmed electrophysiological activity may nevertheless express low surface channel numbers making definitive identification difficult

This, however, is not necessarily straight-forward because many cell lines with confirmed electrophysiological activity may nevertheless express low surface channel numbers making definitive identification difficult. play important roles in a broad range of physiological and pathophysiological processes. Mutations of single ion channel proteins have been demonstrated to be the cause of genetic diseases, collectively known as channelopathies.8For example, mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) lead to cystic fibrosis, whereas various pain syndromes, including congenital indifference to pain and paroxysmal extreme pain disorder, are associated with either loss or gain of function mutations, respectively, in theSCN9Agene encoding the voltage-gated sodium channel Nav1.7. Along with direct effects on the functionality of ion channel subunits or the proteins that regulate them, channelopathies can also result from autoimmune responses 5-(N,N-Hexamethylene)-amiloride to channel proteins.9 == Figure 1. == Market opportunities and global clinical pipeline for ion channel drug targets. (a) Market opportunities for targeting ion channels which represent the second largest membrane protein target class after GPCRs, adapted from Santoset al2017.5(b) Ion channel drugs in development and the clinical pipeline (sourced from Pharmaprojects as of March/April 2016). To date, most ion channel drug development has focused on identifying and developing small molecule and peptide modulators, mainly through serendipitous discovery due to a lack of information on structure and function. Many ion channel modulators have been discovered 5-(N,N-Hexamethylene)-amiloride from studies of naturally occurring substances, such as toxins from plants and venomous animals.10The conotoxin family is the most well-known of the animal-derived toxins,11with ziconotide, a selective Cav2.2 antagonist, a frequently cited example of a synthetic peptide analogue of cone snail -conotoxin used for the treatment of severe chronic pain.12Despite the initial successes in identifying ion channel modulators, only two novel ion channel drugs have been approved by the US Food and Drug Administration (FDA) since the 1990s, despite vastly improved screening tools for small molecule/compound libraries.13The most recently approved drugs are ivacaftor (Kalydeco), which potentiates the cystic fibrosis CFTR chloride channel14and crofelemer (Mytesi), a proanthocyanidin oligomer, which inhibits both CFTR and the calcium-activated chloride 5-(N,N-Hexamethylene)-amiloride channel TMEM16A.15As with the vast majority of other drugs targeting ion channels, ivacaftor and crofelemer are both small molecule chemical entities.16 Alternative modalities for targeting ion channels have recently included monoclonal antibodies (mAbs), but their therapeutic potential has been vastly underexploited.17An in-house analysis using information gleaned from the public domain revealed that only one antibody drug (a polyclonal or pAb) is in early clinical study among the > 650 ion channel targeting drugs under active development in the global pipeline (Figure 1(b)). == Advantages of targeting ion channels with antibodies == Although therapeutic antibodies are typically more expensive to develop, they generally attain higher approval success rates compared with their small molecule counterparts.18As with antibodies targeting GPCRs,19,20antibodies directed towards ion channels have the potential to offer many additional advantages relative to selectivity, bioavailability and effector function as summarized below. == Selectivity == Obtaining target selectivity in small molecule drug discovery is one of the foremost technical hurdles for drug development, regardless of the route 5-(N,N-Hexamethylene)-amiloride from which the molecule is derived, i.e., rational design or random screening of large compound libraries. With respect to ion channels, this has been particularly challenging as ion channels within 5-(N,N-Hexamethylene)-amiloride a given family often share high levels of homology, notably within the pore-forming domains where many channel Rabbit Polyclonal to TK (phospho-Ser13) blockers exert their effect, but have vastly different physiological roles. For example, the sodium channel isoforms Nav1.7, Nav1.8 and Nav1.9 have been identified as targets in nociceptor neurons where modulation ameliorates different pain states. However, stringent counter-screens are required to characterize potential modulators of these channels for effects on other.