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Translation elongation-3-like factors: are they rational antifungal targets?
1Dept of Microbiology, Immunology and Parasitology, Center of Excellence in Oral and Craniofacial Biology, LSU Health Sciences Center - School of Dentistry, 1100 Florida Ave, Box F8-130, New Orleans, LA 70119, USA. jsturt@lsuhsc.edu
Abstract:
The occurrence of fungal infection has escalated significantly in recent years and is expected to continue to increase for the foreseeable future. Unfortunately, only a limited number of antifungal drugs are currently available partially due to a lack of suitable targets. The most commonly used antifungals target the same molecule in the cell membrane and, while efficacious, are either extremely toxic or susceptible to resistance. This article examines elongation factor-3, which is unique to fungi and essential for fungal cell survival and, thus, an attractive antifungal target. A search for inhibitors of this 'perfect target' led to identification of compounds (sordarins) which inhibited elongation factor-2, a protein with a mammalian homologue. Molecular analysis demonstrated why sordarins can specifically act against fungal elongation factor-2. This data questions the validity of pursuing genes as targets only if they are unique to fungi. Proteins that are homologous to elongation factor-3 are also discussed. The advances in molecular techniques and bioinformatics will allow the re-evaluation of targets previously thought to be unattractive. In addition, molecular genetics provides new and novel information on cellular processes that can potentially introduce new targets.
Insights
Fungal infections are rising, but new antifungal drugs are scarce. Researchers explored elongation factor-3 as a potential target, finding compounds that inhibit a related protein, offering new avenues for antifungal drug development.
Area of Science:
- Mycology
- Molecular Biology
- Drug Discovery
Background:
- Rising incidence of fungal infections necessitates novel antifungal therapies.
- Limited availability of current antifungals due to toxicity and resistance.
- Lack of suitable drug targets hinders antifungal drug development.
Purpose of the Study:
- To investigate elongation factor-3 as a potential antifungal target.
- To identify and analyze inhibitors of fungal elongation factors.
- To re-evaluate traditional criteria for antifungal drug target selection.
Main Methods:
- Literature review and analysis of fungal elongation factors.
- Identification of compounds targeting fungal elongation factors.
- Molecular analysis of drug-target interactions.
Main Results:
- Elongation factor-3 is essential for fungal survival and a promising target.
- Sordarins identified as inhibitors, targeting elongation factor-2.
- Molecular analysis revealed specific inhibition of fungal elongation factor-2 over mammalian homologues.
Conclusions:
- Fungal elongation factor-3 presents a viable target for novel antifungal development.
- Inhibitors targeting homologous proteins, like sordarins, can be effective.
- Advances in molecular techniques enable re-evaluation of previously overlooked targets.