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Exploring structure-activity relationships around the phosphomannose isomerase inhibitor AF14049 via combinatorial
A Bhandari1, D G Jones, J R Schullek
1Affymax Research Institute, Palo Alto, CA 94304, USA.
Phosphomannose Isomerase (PMI) is vital for fungal cell walls. A new inhibitor, AF14049, was found and synthesized to study its structure-activity relationship (SAR) for potential antifungal development.
Area of Science:
- Biochemistry
- Mycology
- Medicinal Chemistry
Background:
- Phosphomannose Isomerase (PMI) is a crucial enzyme in fungal cell wall biosynthesis.
- Genetic studies confirm PMI's essential role in maintaining fungal structural integrity.
Purpose of the Study:
- To investigate the structure-activity relationship (SAR) of a novel PMI inhibitor, AF14049.
- To explore the potential of PMI inhibitors as antifungal agents.
Main Methods:
- Discovery of AF14049 as a byproduct of high-throughput screening against Candida albicans PMI.
- Development of solid-phase synthetic methods for analog generation.
- Synthesis of compound libraries and discrete analogs for SAR studies.
Main Results:
- Identification and synthesis of the PMI inhibitor AF14049.
- Exploration of SAR around the AF14049 scaffold.
- Establishment of synthetic routes for novel PMI inhibitors.
Conclusions:
- AF14049 represents a promising starting point for developing new antifungal therapies.
- Further SAR studies are warranted to optimize inhibitor potency and properties.
- Targeting fungal cell wall biosynthesis via PMI inhibition is a viable antifungal strategy.
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