The current treatments for invasive fungal infections are limited to polyenes (amphotericin B derivatives), echinocandins, antimetabolites (flucytosine), and azoles. However, drug toxicity and antifungal resistance often limit the use of these drugs, making it necessary to develop new antifungal therapeutics. Protein farnesyltransferases (FTases, EC 2.5.1.58) have shown to be essential for growth and virulence in several pathogenic fungi, and therefore present a potential target for the discovery of new antifungals. Creative Biolabs offers fully-integrated contract research services for antifungal drug development targeting the FTase.
Introduction of Protein Farnesyltransferase
FTase catalyzes the attachment of the 15-carbon isoprenoid farnesyl pyrophosphate (FPP) to protein substrates that bear the carboxyl-terminal CAAX box motif (C = cysteine; A= aliphatic residues; X = variable residue). Typically, these protein substrates include Ras, Ras homologs, and other small G proteins. This lipidation step is critical for localization of proteins to membranes of cell compartments, where such modified proteins function. FTase is ubiquitously distributed in eukaryotic species but structure-based studies of this enzyme have revealed significant differences between the human and fungal enzymes such as in the substrate- and product-binding regions, which can be exploited for the discovery of species-specific FTase inhibitors to treat fungal infections.
Fig.1 Surface representation of the active site funnels of protein farnesyltransferase from A. fumigatus (AfFTase), C. neoformans (CnFTase, PDB 3Q75), and human (hFTase, PDB 1TN6) viewed from the top of the active site funnel. (Mabanglo, 2014)
Protein Farnesyltransferase as an Antifungal Target
Studies have reported FTase to be essential for certain fungi for viability. Vallim et al. (2004) reported pharmacological inhibition of farnesyltransferase activity resulted in the prevention of the growth and cellular differentiation of C. neoformans. Moreover, they also reported that x-ray structures of FTase of C. neoformans were different from human FTase, providing compelling evidence that the essential FTase of C. neoformans is an attractive drug target. Mabanglo et al. (2014) reported the structure of FTase from the fungal pathogen Aspergillus fumigatus and the results showed that this enzyme also exhibited structural differences from the human enzyme that was sufficient for species-specific inhibition.
Features of Our Services
Creative Biolabs leverages its state-of-the-art technologies, rich antifungal drug discovery expertise, and strong experience in contract research to support the rapidly growing interests in this field. Our service lists cover the largest and most diverse portfolio of standard and custom drug discovery solutions to meet your exact requirements. Moreover, our services are characterized by:
By working with Creative Biolabs, who has been key players in the antifungal drug discovery industry for years, you and your team will be able to bring your valuable medicinal chemistry leads into the pipeline with the highest quality and efficiency. For more information about our services, please do not hesitate to contact us.
References
For Research Use Only.
