Sandbox 123456: Difference between revisions

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==Introduction==

Noxafil, also known as posaconazole, was developed by Schering-Plough in the mid-2000s (acs.org), 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 <ref name=pubchem>National Center for Biotechnology Information. PubChem Compound Database; CID=468595, https://pubchem.ncbi.nlm.nih.gov/compound/468595</ref>.

Noxafil, also known as posaconazole, was developed by Schering-Plough in the mid-2000s <ref name="acs">Posaconazole. (2011, December 12). Retrieved from https://www.acs.org/content/acs/en/molecule-of-the-week/archive/p/molecule-of-the-week-posaconazole.html?_ga=1.240614083.1136742914.1490798730 </ref>, 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 <ref name=pubchem>National Center for Biotechnology Information. PubChem Compound Database; CID=468595, https://pubchem.ncbi.nlm.nih.gov/compound/468595</ref>.

==Function/Structure==

Line 10:

*IUPAC name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one

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 (green link) and that the triazolone sidechain is hydroxylated in the posaconazole structure<ref>PMID: 21059682 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi (formularyjournal.~~com~~).

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 (green link) and that the triazolone sidechain is hydroxylated in the posaconazole structure<ref>PMID: 21059682 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi <ref name="formularyjournal">Sircar-Ramsewak,, F., Nicolau, D. P., & Kuti, J. L. (2005). Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary Journal - Modern Medicine Network </ref>.

(explanation of green links/figures?)

==Mechanism==

When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51) which prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. 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 <ref name="~~soysal~~"~~>doi: 10.2147~~/~~IDR.S65592</ref~~>.

When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51) which prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. 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 <ref name="formularyjournal" />.

== Relevance ==

Invasive fungal infections, commonly caused by "Candida" or "Aspergillus" species affect patients that are immunocompromised such as those.... "Candida" (thrush) is the most common yeast pathogen while Aspergillus is the most common mold pathogen leading to invasive fungal infections <ref name="soysal"/>. 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)<ref>doi: 10.1007/s12281-016-0255-4</ref> . Overall, Noxafil displays fewer cases of invasive fungal infections and is also a more affordable treatment for immunocompromised patients. (Add more & add citations).

Invasive fungal infections, commonly caused by "Candida" or "Aspergillus" species affect patients that are immunocompromised such as those.... "Candida" (thrush) is the most common yeast pathogen while Aspergillus is the most common mold pathogen leading to invasive fungal infections <ref name="soysal">doi: 10.2147/IDR.S65592</ref>. 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)<ref>doi: 10.1007/s12281-016-0255-4</ref> . 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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@@ Line 1: / Line 1: @@
-<Structure load='5FSA' size='350' frame='true' align='right' caption='Crystal structure of sterol 14-alpha demethylase (CYP51) from a pathogenic yeast Candida albicans in complex with the antifungal drug posaconazole' />
+<Structure load='5FSA' size='350' frame='true' align='right' caption='Crystal structure of sterol 14-alpha demethylase (CYP51) from a pathogenic yeast Candida albicans in complex with the antifungal drug posaconazole PDB ID: 5FSA' />
 ==Introduction==
-Noxafil, also known as posaconazole, was developed by Schering-Plough in the mid-2000s (acs.org), 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 <ref name=pubchem>National Center for Biotechnology Information. PubChem Compound Database; CID=468595, https://pubchem.ncbi.nlm.nih.gov/compound/468595</ref>.
+Noxafil, also known as posaconazole, was developed by Schering-Plough in the mid-2000s <ref name="acs">Posaconazole. (2011, December 12). Retrieved from https://www.acs.org/content/acs/en/molecule-of-the-week/archive/p/molecule-of-the-week-posaconazole.html?_ga=1.240614083.1136742914.1490798730 </ref>, 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 <ref name=pubchem>National Center for Biotechnology Information. PubChem Compound Database; CID=468595, https://pubchem.ncbi.nlm.nih.gov/compound/468595</ref>.
 ==Function/Structure==
@@ Line 10: / Line 10: @@
 *IUPAC name: 4-[4-[4-[4-[[(3R,5R)-5-(2,4-difluorophenyl)-5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one
-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 (green link) and that the triazolone sidechain is hydroxylated in the posaconazole structure<ref>PMID: 21059682 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi (formularyjournal.com).
+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 (green link) and that the triazolone sidechain is hydroxylated in the posaconazole structure<ref>PMID: 21059682 </ref>. The extended side chain residues and hydrophobic contacts enhances antifungal activity by allowing tighter binding affinities to the <scene name='75/756730/Hemegroup/1'>heme cofactor</scene> in the active site of CYP450-dependent enzyme lanosterol alpha-demthylase (CYP51) <ref name="groll">doi:10.1586/14787210.3.4.467</ref><ref>doi: 10.1086/523576</ref>. The tighter binding affinity of posaconazole makes it less susceptible to be affected by mutations in the enzyme resulting in resistance of fungi <ref name="formularyjournal">Sircar-Ramsewak,, F., Nicolau, D. P., & Kuti, J. L. (2005). Focus on posaconazole: A novel triazole antifungal for the treatment of invasive fungal infections. Formulary Journal - Modern Medicine Network </ref>.
 (explanation of green links/figures?)
 ==Mechanism==
-When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51) which prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. 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 <ref name="soysal">doi:  10.2147/IDR.S65592</ref>.
+When administered, posaconazole acts as a potent and broad-spectrum antifungal drug by binding to the heme cofactor (make green link) located in the active site of CYP450-dependent enzyme lanosterol alpha-demethylase (CYP51) which prevents biosynthesis of ergosterol and causes accumulation of toxic methylated sterol precursor, 14-alpha-methylsterol <ref name="groll"/>. 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 <ref name="formularyjournal" />.
 == Relevance ==
-Invasive fungal infections, commonly caused by "Candida" or "Aspergillus" species affect patients that are immunocompromised such as those.... "Candida" (thrush) is the most common yeast pathogen while Aspergillus is the most common mold pathogen leading to invasive fungal infections <ref name="soysal"/>. 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)<ref>doi:  10.1007/s12281-016-0255-4</ref> . Overall, Noxafil displays fewer cases of invasive fungal infections and is also a more affordable treatment for immunocompromised patients. (Add more & add citations).
+Invasive fungal infections, commonly caused by "Candida" or "Aspergillus" species affect patients that are immunocompromised such as those.... "Candida" (thrush) is the most common yeast pathogen while Aspergillus is the most common mold pathogen leading to invasive fungal infections <ref name="soysal">doi:  10.2147/IDR.S65592</ref>.  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)<ref>doi:  10.1007/s12281-016-0255-4</ref> . Overall, Noxafil displays fewer cases of invasive fungal infections and is also a more affordable treatment for immunocompromised patients. (Add more & add citations).
 == References ==
 <references/>