Empowered by leading technologies as well as years of experience in drug discovery, Creative Biolabs provides antifungal drug discovery services for our clients. Here is an introduction about sphingolipid biosynthesis, which is considered to be a potential target for antifungal drug discovery.
Current Situation of Antifungal Drug Research
During the last few decades, fungi have become an increasing concern due to the rise in cases of infection. The need for effective treatments against fungal disease is clear but, unfortunately, the availability of antifungal drugs is limited. Only a few classes of antifungal drugs have been developed, such as fluoropyrimidine analogs, polyenes, azoles, and echinocandins, directly targeting different fungal structures. The most recently discovered class, echinocandins, was approved in the 2000s and since then, no new class of drug has been developed. Moreover, the currently used antifungal agents display a low efficacy in killing fungal cells and are highly toxic, due to the similarities between fungi and mammals at the biochemical and biological level. For these reasons, the discovery of new targets and drugs for the treatment of fungal diseases is an urgent necessity, but it is also a challenge for scientists in the area of mycology.
Biosynthesis of Sphingolipids in Fungi
Sphingolipids are present in eukaryotic cells, such as mammals and fungi. Although the most frequent sphingolipid in mammalian cells is sphingomyelin, there are two main groups described in fungal cells, IPCs and hexosylceramides, such as GlcCer and GalCer. The first step of sphingolipids biosynthesis is conserved among mammalian, fungi, and plants, starting by the condensation of serine to palmitoyl-CoA, forming 3-keto-dihydrosphingosine and then dihydrosphingosine through a reduction reaction. From sphingosine, fatty acids are transferred to the structure to form ceramide or phytoceramide, the latter being known to present very long chain fatty acids (C24 or C26) and to be exclusive to fungi. From these two structures, IPCs and GlCer are formed.
Fig.1 Outlines of sphingolipid metabolic pathways. (Rollin-Pinheiro, 2016)
Targeting the Biosynthesis of Fungal Sphingolipids
Sphingolipid biosynthesis is extremely important to understand the role of sphingolipids in fungal cells and has also contributed to the discovery of inhibitors of the sphingolipid biosynthetic pathway. Along with the biosynthetic pathway of sphingolipids, many inhibitors have been known and some of them are related to the antifungal activity.
As the current antifungal therapies available today present many limitations and the need for new alternatives for fungal infection treatments is undeniable, the interest in using sphingolipids as a target for new drugs has finally increased. The fungal sphingolipid pathway represents a unique platform to exploit for the R&D of new antifungal compounds, particularly against IPCs and GlcCer synthesis. Both natural and synthetic fungal inhibitors have been identified and the R&D of these inhibitors has been significantly intensified during the last decade.
With the help of our well-established technologies and experienced scientists, Creative Biolabs provides antifungal drug discovery services 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. Besides, we are open to discussions. Please do not hesitate to contact us for more information.
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