Invasive fungal infections caused by fungal pathogens have been emerging as a global problem of great concern as they are associated with increased morbidity and mortality. However, limited drugs of choice are available for fungal infection treatment. To make matters worse, continuous drug usage has led to resistance, making it necessary to develop new antifungal drugs. Due to their vital roles for fungi growth and the establishment in the host, fungal enzymes represent one of the most important and potential targets for drug development. Creative Biolabs offers a range of antifungal drug discovery services. Here, we introduce Ketol-acid reductoisomerase as a suitable target for antifungal drug development to manage fungal infections, such as Aspergillus.
Introduction of Ketol-Acid Reductoisomerase
Enzymes that catalyze amino acid biosynthesis pathway of fungi are identified as putative targets for antifungal drugs because they are critical for amino acid biosynthesis and they are highly conserved in fungi. Ketol-acid reductoisomerase (KARI; EC 1.1.1.86) is such an enzyme that is involved in the biosynthetic pathway for branched-chain amino acids (valine, leucine, isoleucine) in fungi but not in animals, making it an attractive target for antifungal drug discovery. They catalyze the conversion of either 2-acetolactate or 2-Aceto-2-hydroxybutyrate to their corresponding 2,3-dihydroxy-3-allyl butyrate products. For the reaction catalyzed by KARI, Mg++ and NADPH are required as cofactor and coenzyme respectively.
Fig.1 Biosynthetic pathways for branched-chain amino acids catalyzed by KARI. (Chen, 2018)
KARI as an Antifungal Drug Discovery Target
As KARI catalyzes the second important step in the biosynthesis of the branched-chain amino acids and the absence of this enzyme in animals, it is recognized as an ideal target to design non-toxic KARI inhibitors as potential novel drugs. Structure-based drug design method is often used for this attempt. Inhibitors such as HOE 704, IpOHA, 1,2,3-thiadiazoles, and CPD derivatives have been shown to be potential KARI inhibitors. HOE 704 and IpOHA can inhibit tuberculosis as was reported in some literature, and CPD had good antifungal activities as well. Besides, Srinivasan et al. (2001) reported the screening and evaluation of inhibitors for the development of drugs against Aspergillus. Liu et al. (2009) reported the synthesis of cyclopropanecarboxamide that shows good in vivo fungicidal activity against F. oxysporum at a concentration of 500 μg/mL.
Features of our Services
As a well-trusted drug discovery and development company, Creative Biolabs offers fully-integrated contract research services for antifungal drug development, including target identification and validation, hit identification, hit to lead, lead optimization, and IND-enabling services. We provide services characterized by:
Empowered by leading technologies as well as abundant experience in the field of antifungal drug discovery, Creative Biolabs is providing high-quality contract services to aid in the discovery of new antifungal drugs against a wide spectrum of potential targets. For more information, please contact us to discuss your requirements.
References
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