ifungal drugs include azoles, allylamines and the macrolides amphotericin and nystatin, all of which are thought to act mainly via effects on ergosterol. Other drugs include pyrimidine analogues which affect protein synthesis, and sulphonamides. These drugs often have limited efficacy together with substantial MedChemExpress KPT-9274 side-effects, and emergence of drug resistance is an increasing problem. New drugs to treat fungal infections are therefore needed. In many organisms K+, Ca2+ and Trp channels are essential components of cellular signalling and homeostatic pathways, and they are drug targets in humans. While the human genome contains genes encoding at least 78 K+ channel subunits, 11 Cav channel a-subunits and more than 30 Trp channel subunits, the genomes of pathogenic fungi each contain only very small numbers of genes encoding homologues of cation channel subunits. This striking lack of redundancy amongst cation channels in pathogenic fungi suggests that they 
might be effective therapeutic targets. Furthermore, some anti-fungal drugs affect K+, Ca2+ or Trp channel function. For example, azole drugs such as clotrimazole inhibit Trp channels, K+ channels and Ca2+ channels. Although they have sequence motifs similar to mammalian K+ channels, and two pore domains similar to human two-pore K+ channel subunits, the fungal homologues of TOK1 have a topology and putative structure that is unique to fungi. They are also likely to have a unique gating mechanism. These factors suggest that they may be attractive pharmacological targets. This suggestion gains some support from evidence that a viral toxin that activates TOK1 in S. cerevisiae causes cell death, due to excessive K+ flux, and a TOK1 homologue in C. albicans increases sensitivity to human salivary histatin-5. Activators or inhibitors of TOK1 homologues may therefore be novel antifungals. A diverse range of agents affecting Ca2+ channels or Ca2+ signalling pathways are also toxic to fungi, and Ca2+ channels are involved in the survival of fungal cells after azoleinduced stress. The differing pore sequences of human Cav channels and fungal homologues of Cch1 suggest that analogues of Cav channel modulators, which often bind within the pore region, may exhibit selectivity for fungal Cch1 homologues over Cav channels. Mitochondrial Ca2+ PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/22203538 uptake may be involved in the anti-fungal effects of some peptides Cation Channels in Human Pathogenic Fungi and mitochondrial function is linked to drug sensitivity in several fungi, suggesting that fungal homologues of MCU may be attractive novel targets for anti-fungal drugs. Ru360 is a potent inhibitor of MCU, and analogues of this drug might possess selective anti-fungal properties against those fungi that contain genes encoding MCU homologues, such as Aspergillus spp. and Cryptococcus spp. Pharmacological modulators of Trp channel function, which are increasingly being developed as potential therapeutic drugs against human targets, may also show anti-fungal activity via effects on fungal homologues of Trp channels. Indole and other aromatic compounds such as quinoline and parabens activate TrpY1 and may potentially have antifungal activity. This study presents the opportunity for cloning and functional characterization of cation channels in pathogenic fungi, and suggests that rational design of drugs targeted against these channels may be an effective route to new therapies. Materials and Methods Genomes Analyzed The genomes of the following pathogenic fungi w
