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Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole.

Figure 1
<div class='caption-title'>Spectral characterization of CYP51Tc and CYP51Tb.</div>
<div class='caption-title'>Overall structures of CYP51.</div>
Chen CK, Leung SS, Guilbert C, Jacobson MP, McKerrow JH, Podust LM
OpenAccess logo PLoS Negl Trop Dis 4 e651 (2010)
Related entries: 2wuz, 2wv2, 2x2n

Cited: 70 times
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Abstract

Background

Chagas Disease is the leading cause of heart failure in Latin America. Current drug therapy is limited by issues of both efficacy and severe side effects. Trypansoma cruzi, the protozoan agent of Chagas Disease, is closely related to two other major global pathogens, Leishmania spp., responsible for leishmaniasis, and Trypansoma brucei, the causative agent of African Sleeping Sickness. Both T. cruzi and Leishmania parasites have an essential requirement for ergosterol, and are thus vulnerable to inhibitors of sterol 14alpha-demethylase (CYP51), which catalyzes the conversion of lanosterol to ergosterol. Clinically employed anti-fungal azoles inhibit ergosterol biosynthesis in fungi, and specific azoles are also effective against both Trypanosoma and Leishmania parasites. However, modification of azoles to enhance efficacy and circumvent potential drug resistance has been problematic for both parasitic and fungal infections due to the lack of structural insights into drug binding.

Reviews - 2wx2 mentioned but not cited (2)

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  2. The Potential of Secondary Metabolites from Plants as Drugs or Leads against Protozoan Neglected Diseases-Part III: In-Silico Molecular Docking Investigations. Ogungbe IV, Setzer WN. Molecules 21 E1389 (2016)

Articles - 2wx2 mentioned but not cited (8)

  1. Structural Insights into Binding of the Antifungal Drug Fluconazole to Saccharomyces cerevisiae Lanosterol 14α-Demethylase. Sagatova AA, Keniya MV, Wilson RK, Monk BC, Tyndall JD. Antimicrob Agents Chemother 59 4982-4989 (2015)
  2. Structural characterization of CYP51 from Trypanosoma cruzi and Trypanosoma brucei bound to the antifungal drugs posaconazole and fluconazole. Chen CK, Leung SS, Guilbert C, Jacobson MP, McKerrow JH, Podust LM. PLoS Negl Trop Dis 4 e651 (2010)
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Reviews citing this publication (16)

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  14. Synthesis and Biological Activity of Sterol 14α-Demethylase and Sterol C24-Methyltransferase Inhibitors. Leaver DJ. Molecules 23 E1753 (2018)
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  9. Aspergillus fumigatus harbouring the sole Y121F mutation shows decreased susceptibility to voriconazole but maintained susceptibility to itraconazole and posaconazole. Lescar J, Meyer I, Akshita K, Srinivasaraghavan K, Verma C, Palous M, Mazier D, Datry A, Fekkar A. J Antimicrob Chemother 69 3244-3247 (2014)
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  41. Anti-Trypanosoma cruzi Activity, Mutagenicity, Hepatocytotoxicity and Nitroreductase Enzyme Evaluation of 3-Nitrotriazole, 2-Nitroimidazole and Triazole Derivatives. Menozzi CAC, França RRF, Luccas PH, Baptista MDS, Fernandes TVA, Hoelz LVB, Sales Junior PA, Murta SMF, Romanha A, Galvão BVD, Macedo MO, Goldstein ADC, Araujo-Lima CF, Felzenszwalb I, Nonato MC, Castelo-Branco FS, Boechat N. Molecules 28 7461 (2023)
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  44. In Silico Antiprotozoal Evaluation of 1,4-Naphthoquinone Derivatives against Chagas and Leishmaniasis Diseases Using QSAR, Molecular Docking, and ADME Approaches. Prieto Cárdenas LS, Arias Soler KA, Nossa González DL, Rozo Núñez WE, Cárdenas-Chaparro A, Duchowicz PR, Gómez Castaño JA. Pharmaceuticals (Basel) 15 687 (2022)


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