• DOI:10.4155/fmc-2016-0110
• Corpus ID: 30291126

The GPI anchor pathway: a promising antifungal target?

@article{Mutz2016TheGA,
  title={The GPI anchor pathway: a promising antifungal target?},
  author={Mitchell W. Mutz and Terry Roemer},
  journal={Future medicinal chemistry},
  year={2016},
  volume={8 12},
  pages={
          1387-91
        }
}

• M. Mutz, T. Roemer
• Published 11 August 2016
• Biology
• Future medicinal chemistry

A key challenge with developing antifungal drugs is that both humans and fungi are eukaryotic organisms; as a result, antifungal therapeutics may have substantial toxicity due to inhibition of closely related human targets. Compounding this challenge, the principal clinically relevant fungal pathogens Aspergillus fumigatus and Candida albicans diverged from a common ancestor 1 billion years ago [1], underscoring their substantial genetic and pathogenic diversity and the difficulty of new antifungal agents achieving broad-spectrum activity. Identifying therapeutics that can both overcome this diversity as well as remain well tolerated in human subjects has proven elusive. As a result, there are only three mechanistically distinct classes of antifungal therapeutics that are currently employed to treat serious life-threatening infections due to both yeast and molds. There have been multiple ‘calls to action’ for the development of new antifungal therapeutics and many discussions of what the optimal properties of the ‘ideal’ therapeutic might be: 1) activity against fungi that are intrinsically resistant to currently marketed antifungal agents; 2) broad-spectrum activity, especially versus a wide array of molds that are difficult to diagnose in the clinic; 3) no cross resistance with current antifungals; 4) the ability to bolster the immune response to combat mycoses; and 5) fungicidal activity [2,3]. Within this framework, recent work on inhibitors of glycosylphosphatidylinositol (GPI) biosynthesis will be considered for their potential as new entrants in the antifungal armamentarium. With the increased prevalence of drug-resistant species of both yeasts and molds as causative pathogens of invasive, life-threatening infections, there have been renewed efforts to identify novel, broad-spectrum antifungal agents that can provide therapeutic benefit to improve clinical outcomes. GPI biosynthesis is a conserved and essential process that is required for cell wall biogenesis in both yeasts and molds [4,5]. The role of GPI in anchoring proteins to the outer wall of fungi underscores its function in maintaining cell wall integrity [6]. Due to the prevalence of this pathway in fungal species, GPI biosynthesis presents an attractive target for the development of a broad-spectrum antifungal compound that is also a cell wall active agent. Indeed, numerous cell wall anchored proteins have been identified that rely on the GPI post-translational modification for cell surface localization (Saccharomyces cerevisiae has ∼60) and chemical genetics approaches have proven highly successful in identifying these GPI-anchored proteins as well as cognate small molecule inhibitors of GPI biosynthesis [7,8]. The structures of known GPI pathway inhibitors described herein as well as a representation of the GPI precursor and enzymatic steps of GPI biosynthesis are shown in Figure 1. However, as orthologous GPI biosynthetic enzymes exist in man, fungal specificity of such agents remains an important consideration. “The activity of Gwt1 inhibitors as well as Mcd4 inhibitors versus a broad range of yeast and molds and lack of observed cross-resistance with existing therapeutics should encourage further investigation for novel antifungal leads targeting GPI biosynthesis.” Special Focus Issue – Antifungal Drug Discovery