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IntroductionNoxafil, also known as posaconazole, was developed by Schering-Plough in the mid-2000s [1], and is a broad spectrum antifungal drug mainly used to treat fungal infections caused by Candida and Aspergillus species. Noxafil is also often used when other antifungal medicines are not able to be tolerated or if the patient is immunocompromised. Noxafil falls under the triazole class of antifungal drugs and thus works through inhibiting the biosynthesis of ergosterol in the fungal cell membrane, an essential factor that if inhibited, will lead to prevention of cell growth and ultimately death [2].
Function/Structure
The primary component of Noxafil, posaconazole (green link) is a potent, broad-spectrum antifungal drug. It was derived from a similar triazole antifungal agent, Itraconazole. The differences in structure are that the chlorine substituents in the aromatic ring on the left-hand side of the images are replaces with fluorines and that the triazolone sidechain is hydroxylated in the posaconazole structure[3]. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the in the active site of the CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) [4][5]. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi [6]. The scene shows the crystal of sterol 14-alpha demethylase (CYP51) from a pathogenic yeast Candida albicans in complex with the antifungal drug posaconazole
MechanismWhen administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor through an ionic bond between a neutral nitrogen atom on posaconazole and an iron atom on heme (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51). This prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol [4]. Ergosterol is an essential performs in fungal cells how cholesterol does in animal cells, making the cell membrane less permeable. Without it, the cells can no longer proliferate and eventually die because the cell membranes become “leaky”, releasing essential organic components from the cell’s interior and preventing it from performing normal cellular functions (citation?). In this way, posaconazole acts as a fungistatic against "Candida" species, and a fungicidal against "Asperigillus" species [6]. RelevanceInvasive fungal infections, commonly caused by "Candida" or "Aspergillus" species affect patients that are immunocompromised such as those with different pre-existing infections or more seriously for those with immunologically suppressing diseases like HIV/AIDS. "Candida" (thrush/Candidiasis) is the most common yeast pathogen that typically grows in human mucosal surfaces like the intestinal tract and causes pathology when it becomes overgrown. "Aspergillus" is the most common mold pathogen leading to invasive fungal infections, termed Aspergillosis, when it is acquired from the surrounding environment [7]. Noxafil oral suspension is the best form of treatment for invasive Candida and Aspergillus infections in patients 13 years and older who are severely immunocompromised. Noxafil is also more effective at preventing invasive fungal infections in immunocompromised patients when compared to other antifungal treatments (fluconazole and itraconazole)[8] . Overall, Noxafil displays fewer cases of invasive fungal infections and is also a more affordable treatment for immunocompromised patients. (Add more & add citations).
References
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