Clinically available antifungals for the treatment of invasive fungal infections often suffer from low bioavailability, toxicity, and drug resistance. These issues emphasize an urgent need for novel antifungal agents with improved properties or novel mechanisms of action targeting new pathways such as the nucleic acid biosynthesis. Creative Biolabs, with years of experience in the field of drug discovery, is now providing a full portfolio of services for antifungal drug development against diverse targets, including the nucleic acid synthesis pathway.
Dihydroorotate Dehydrogenase as an Antifungal Target
Dihydroorotate dehydrogenase (DHODH) is an oxidoreductase that catalyzes the fourth step of the pyrimidine biosynthesis pathway, the conversion of dihydroorotate to orotate. DHODH has been validated as an effective target for antifungal drug discovery. Studies have reported the discovery of F901318, a member of the orotomide class of antifungal agents, as an inhibitor of DHODH. The antifungal activity of F901318 appears to be fungi-specific with significantly more potent activity against fungal DHODH than human DHODH. F901318 has demonstrated potent in vitro activity against various molds and endemic fungi. This drug has moved into clinical trials.
Fig.1 Binding of F901318 to Aspergillus fumigatus DHODH. (Oliver, 2016)
Thymidylate Synthase as an Antifungal Target
Thymidylate synthetase (TS) is an enzyme that is involved in DNA synthesis and the nuclear division process. Targeting TS has been validated as an effective strategy for antifungal drug discovery. Flucytosine, a pyrimidine analog, was first developed as an anticancer agent but later on, it was screened for an antifungal agent, and today it is used in combination therapy in clinical due to resistance. It can be converted into 5-fluorouracil, which is then incorporated into RNA, causing premature chain termination. Moreover, it inhibits DNA synthesis through effects on TS.
Features of our Services
Besides these two enzymes, nucleic acid synthesis pathway involves a great variety of factors and pathways, Creative Biolabs can also customize the services against other targets that interfere with DNA, RNA, and relevant factors (such as enzymes and transcription factors).
At Creative Biolabs, we take a comprehensive approach for your antifungal drug development. Leveraging our state-of-the-art facilities and a strong understanding of the drug discovery process, we design and perform custom-specific programs to offer the best solutions. Moreover, our services are characterized by:
Services ranging from target identification and validation, Hit identification, Hit to lead, Lead optimization, and IND enabling, we can provide both full-service packages and stand-alone services. For more information about our services, please do not hesitate to contact us.
Reference
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