After years of hard working in the drug discovery field, Creative Biolabs has got an in-depth study about calcium-calcineurin signaling pathway and vital molecular that influences biological progress in vivo. We offer several antifungal drug target discovery services against calcium-calcineurin signaling pathway.
Calcium-Calcineurin Signaling Pathway
The emergence of fungal resistance has become frequent recently. The limited selection of antifungal drugs for clinical fungal infection therapy forces us to search for new antifungal targets that can be used for new antifungal drugs discovery. Calcium, which acts as a messenger in both mammals and fungi, plays direct roles in controlling the expression patterns of its signaling systems and in cell survival. In addition, calcium and calcineurin in the fungal calcium signaling pathway mediate fungal resistance to antifungal drugs.
The calcium-calcineurin signaling pathway consists of various channels, transporters, pumps, and other proteins or enzymes. Lack of some of these components means sensitization to antifungal drugs. In addition, many researchers have identified efficient compounds that exhibit antifungal activity by themselves or in combination with antifungal drugs by targeting some of the components in the fungal calcium-calcineurin signaling pathway. This targeting disrupts Ca2+ homeostasis, which suggests that this pathway contains potential antifungal targets for the development of new antifungal drugs.
Fig.1 The description of calcium-calcineurin signaling pathway in fungal cells. (Liu, 2015)
Potential Antifungal Targets in Calcium-Calcineurin Signaling Pathway
Calcium is a highly versatile intracellular signal that can regulate many different cellular functions, such as cell differentiation, division, cell-cell fusion, endocytosis, and mating morphogenesis. A small increase in the intracellular calcium concentration can trigger a variety of cellular responses, such as the activation of pathways that control ion channel activity, secretion and gene transcription. Specific inhibitors of fungal Ca2+ channels, such as calmodulin, calcineurin, or other yet unknown components of the CCS pathway, could greatly improve the efficacy of existing antifungal therapies.
Fig.2 The potential targets in calcium-calcineurin signaling pathway and some compounds exhibiting antifungal activity by themselves or in combination with antifungal drugs by interfering with these potential targets. (Liu, 2015)
The concentration of calcium in fungal cells may increase in response to external or internal stresses, leading to a variety of intracellular responses, such as the opening of calcium channels and exchangers on the plasma membrane or endomembrane system. These calcium channels or exchangers and their genes significantly contribute to the cytosolic calcium concentration fluctuation, and the deletion of some calcium signaling components is detrimental to fungal survival. Thus, interfering with the influx or uptake of calcium through the channels or transporters to disturb the calcium homeostasis may benefit fungicidal activity.
Calcium channel blockers, which exert their functions by inhibiting the VGCC on the plasma membrane of mammalian cells, have been the intensive focus of research that by examined genes related to the fungal Ca2+ influx system because of the homology of calcium channels between the fungi and mammals.
The calcium secretory system also plays important roles in maintaining normal cytosol Ca2+ concentrations by releasing or sequestrating Ca2+ in a secretory Ca2+ reservoir. Therefore, agents that interfere with the secretory system may impair fungal cells.
The calcium signaling transduction system includes enzymes and proteins that have been shown to be nonessential for normal growth but critical in mediating cell survival in response to stress. Calcineurin-mediated resistance has been considered one of the important factors in clinical treatment failure against mycoses, and its activation is evoked by calcium-binding protein calmodulin. Therefore, inhibiting calmodulin, calcineurin activity has been extensively studied to reverse antifungal resistance and increase the antifungal activity of existing antifungal drugs.
Calmodulin is a small calcium-binding protein that participates in the transduction of calcium ions to its effector proteins. An increase in the calcium concentration to approximately 10-5 M results in the binding of three calcium ions to fungal calmodulin. Ca2+-calmodulin then specifically binds to calcineurin, leading to its activation to regulate the stress response. Therefore, preventing calmodulin from exerting its function may perturb Ca2+ homeostasis.
Calcineurin is a major protein phosphatase that is responsible for maintaining calcium homeostasis by activating downstream events, and calcineurin-mediated fungal resistance to fungicides constitutes cause for concern.
Features of Our Services
With the help of our well-established technologies and experienced scientists, Creative Biolabs is capable to offer and apply the necessary knowledge and technologies for antifungal drug discovery. We provide very flexible options for each specific case. We are happy to make it accessible to all kinds of research and industrial customers. Please do not hesitate to contact us for more information.
Reference
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