Creative Biolabs has successfully launched an innovative anti-fungal drug platform with multiple high-end technologies. With experienced scientists, we offer a range of targets development services for antifungal drug discovery, including fungal nucleic acid and protein biosynthesis targets.
Potential Fungal Targets
Over the past few decades, around 1.5 to 2 million deaths have been reported every year worldwide because of fungal infections. Immuno-compromised patients are at greater risk of fungal infections and effectiveness of the available drugs is a major concern in their treatment. Furthermore, the majority of drugs face the problem of increasing resistance development in pathogens, narrow spectrum activity, less clinical efficacy and acute as well as chronic side effects. In general, the main fungal targets are cell wall polymer (glucans, chitin, mannoproteins), cell membrane, especially ergosterol biosynthesis, DNA and protein synthesis (topoisomerases, nucleases, elongation factors, and myristoylation), as well as signal transduction pathways (protein kinases and protein phosphatases). Azoles, echinocandins, polyenes, allylamines are the main classes of antifungals in clinical use.
Fig.1 Targets for antifungal therapy. (Kathiravan, 2012)
Several well-characterized compounds are known to inhibit RNA polymerases and elongation factors required for transcription and protein synthesis. Clancy et al. investigated the in vitro antifungal activity of amphotericin B both alone and in combination with rifabutin, an inhibitor of bacterial RNA polymerase, against 26 clinical isolates of Aspergillus and 25 clinical isolates of Fusarium. Synergy or additivity activity between these drugs was demonstrated against all isolates tested, suggesting that inhibition of fungal RNA could be a potential target. Recently, research also showed that sordarin blocks the elongation cycle at the initial steps of translocation, prior to GTP hydrolysis, prevent the formation of peptidyl-[(3)H]puromycin on polysomes from C. albicans. Sordarins are known to be a family of drugs of distinct medical interest.
Several well-characterized compounds are known to inhibit nucleases and topoisomerases required for DNA synthesis. Topoisomerases control the topological state of DNA by introducing transient DNA breaks (single-strand DNA for Type 1 and double-strand DNA for type 2) that allow for manipulation of DNA strands relative to one another. Topoisomerases stabilize the nicked DNA strands by forming a covalent phosphate-tyrosine linkage with either the end of DNA. Topoisomerases-specific inhibitors stabilize this covalent protein-DNA linkage, effectively showing the relegation phase of catalysis and ultimately leading to DNA damage and cell death.
The signal transduction (protein kinases and protein phosphatases) cascades in fungi have become very attractive since their components are now emerging as targets for new natural products, such as cyclosporine A, FK506, rapamycin, wortmannin, and geldanamycin.
Potential Fungal Nucleic Acid And Protein Biosynthesis Targets
With the help of our well-established technologies and experienced scientists, Creative Biolabs is able to further develop the antifungal drug discovery service with a new mechanism of action different from those currently in use. 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 don’t hesitate to contact us for more information.
Reference
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