Progress on antifungal drug targets and inhibitors

XU Bo; JIANG Yan; ZHANG Wan-nian; SHENG Chun-quan

doi:10.3969/j.issn.1006-0111.2013.05.001

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Volume 31 Issue 5

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Article Navigation > Journal of Pharmaceutical Practice and Service > 2013 > 31(5): 321-325,379

XU Bo, JIANG Yan, ZHANG Wan-nian, SHENG Chun-quan. Progress on antifungal drug targets and inhibitors[J]. Journal of Pharmaceutical Practice and Service, 2013, 31(5): 321-325,379. doi: 10.3969/j.issn.1006-0111.2013.05.001

Citation:

XU Bo, JIANG Yan, ZHANG Wan-nian, SHENG Chun-quan. Progress on antifungal drug targets and inhibitors[J]. Journal of Pharmaceutical Practice and Service, 2013, 31(5): 321-325,379. doi: 10.3969/j.issn.1006-0111.2013.05.001

Progress on antifungal drug targets and inhibitors

doi: 10.3969/j.issn.1006-0111.2013.05.001

1.
School of Pharmacy, Second Military Medicinal University, Shanghai 200433, China;Chongming Substation, Shanghai Food and Drug Administration, Shanghai 202150, China
2.
School of Pharmacy, Second Military Medicinal University, Shanghai 200433, China

Received Date: 2012-12-14
Rev Recd Date: 2013-04-08

Abstract

Objective To review recent progress of antifungal drug targets and their inhibitors. Methods Literatures in recent five years were analyzed in combination of the authors'own research work and recent developments of antifungal targets and inhibitors were summarized. Results Current research focused on lanosterol 14-demethylase, β-1,3-glucan synthase, N-myristoyltransferase and secreted aspartic protease. The inhibitors of these targets showed promising future for the development of new antifungal drugs. Conclusion Optimizing the chemical structures of current antifungal agents and discover lead compounds with novel mode of action are of great importance to develop new generation of antifungal agents.
- antifungal drug targets,
- lanosterol 14-demethylase,
- β-1,3-glucan synthase,
- N-myristoyltransferase,
- Secreted aspartic protease

References

[1]	Brown GD,Denning DW,Levitz SM.Tackling human fungal infections[J].Science,2012,336(6082):647.
[2]	Lai CC,Tan CK,Huang YT,et al.Current challenges in the management of invasive fungal infections[J].J Infect Chemother,2008,14(2):77.
[3]	Park BJ,Wannemuehler KA,Marston BJ,et al.Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS[J].AIDS. 2009, 23(4):525.
[4]	Sheng C,Zhang W.New lead structures in antifungal drug discovery[J].Curr Med Chem.2011,18(5): 733.
[5]	Liu J,Balasubramanian MK.1,3-beta-Glucan synthase:a useful target for antifungal drugs[J].Curr Drug Targets Infect Disord.2001,1(2):159.
[6]	Kondoh O, Inagaki Y, Fukuda H,et al.Piperazine propanol derivative as a novel antifungal targeting 1,3-beta-D-glucan synthase[J].Biol Pharm Bull, 2005,28(11):2138.
[7]	Ting PC,Kuang R,Wu H,et al.The synthesis and structure-activity relationship of pyridazinones as glucan synthase inhibitors[J].Bioorg Med Chem Lett.2011,21(6):1819.
[8]	Zhou G,Ting PC,Aslanian R,et al.SAR studies of pyridazinone derivatives as novel glucan synthase inhibitors[J].Bioorg Med Chem Lett.2011,21(10):2890.
[9]	Guinea J,Recio S,Escribano P,et al.In vitro antifungal activities of isavuconazole and comparators against rare yeast pathogens[J].Antimicrob Agents Chemother.2010,54(9):4012.
[10]	Miller JL,Schell WA,Wills EA,et al.In vitro and in vivo efficacies of the new triazole albaconazole against Cryptococcus neoformans[J].Antimicrob Agents Chemother,2004,48(2):384.
[11]	Sheng C,Zhang W,Zhang M,et al.Homology modeling of lanosterol 14-demethylase of Candida albicans and Aspergillus fumigatus and insights into the enzyme-substrate interactions[J].J Biomol Struct & Dyn,2004,22(1):91.
[12]	Sheng C,Wang W,Che X,et al.Improved model of lanosterol 14alpha-demethylase by ligand-supported homology modeling: validation by virtual screening and azole optimization[J].Chem Med Chem,2010,5(3):390.
[13]	Sheng C,Miao Z,Ji H,et al.Three-dimensional model of lanosterol 14 alpha-demethylase from Cryptococcus neoformans: active-site characterization and insights into azole binding[J].Antimicrob Agents Chemother,2009,53(8):3487.
[14]	Sheng C,Che X,Wang W,et al.Design and synthesis of novel triazole antifungal derivatives by structure-based bioisosterism[J].Eur J Med Chem,2011,46(11):5276.
[15]	Sheng C,Che X,Wang W,et al.Structure-based design,synthesis,and antifungal activity of new triazole derivatives[J].Chem Biol Drug Des,2011,78(2):309.
[16]	Wang W,Wang S,Liu Y,et al.Novel conformationally restricted triazole derivatives with potent antifungal activity[J].Eur J Med Chem. 2010,45(2):6020.
[17]	Sun N,Wen J,Lu G,et al.An ultra-fast LC method for the determination of iodiconazole in microdialysis samples and its application in the calibration of laboratory-made linear probes[J].J Pharm Biomed Anal,2010,51(1):248.
[18]	Weston SA,Camble R,Colls J,et al.Crystal structure of the anti-fungal target N-myristoyl transferase[J].Nat Struct Biol,1998,5(3):213.
[19]	Sogabe S,Masubuchi M,Sakata K,et al.Crystal structures of Candida albicans N-myristoyltransferase with two distinct inhibitors[J].Chem Biol,2002,9(10):1119.
[20]	Farazi TA,Waksman G,Gordon JJ. The biology and enzymology of protein N-myristoyla[J].J Biol Chem,2001,276(43):39051.
[21]	Yamazaki K,Kaneko Y,Suwa K,et al.Synthesis of potent and selective inhibitors of Candida albicans N-myristoyltransferase based on the benzothiazole structure[J].J Biol Chem,2005,13(7):2509.
[22]	Ebara S,Naito H,Nakazawa K,et al.FTR1335 is a novel synthetic inhibitor of Candida albicans N-myristoyltransferase with fungicidal activity[J].Biol Pharm Bull,2005,28(4):591.
[23]	Sheng C,Zhu J,Zhang W,et al.3D-QSAR and molecular docking studies on benzothiazole derivatives as Candida albicans N-myristoyltransferase inhibitors[J].Eur J Med Chem,2007,42(4):477.
[24]	Sheng C,Xu H,Wang W,et al.Design, synthesis and antifungal activity of isosteric analogues of benzoheterocyclic N-myristoyltransferase Inhibitors[J].Eur J Med Chem,2010,45(9):3531.
[25]	盛春泉,张万年,王文雅,等. 取代四氢咔唑类抗真菌化合物及其制备方法[P].中国专利,201110094585.4,2011-04-15.
[26]	Cutfield SM,Dodson EJ,Anderson BF,et al.The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors[J].Structure,1995,3(11):1261.
[27]	Stewart K,Abad-Zapatero C.Candida proteases and their inhibition: prospects for antifungal therapy[J].Curr Med Chem,2001,8(8):941.[JP2]
[28]	Degel B,Staib P,Rohrer S,et al.Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2[J].Chem Med Chem 2008,3(2):302.
[29]	Trabocchi A,Mannino C,Machetti F,et al.Identification of inhibitors of drug-resistant Candida albicans strains from a library of bicyclic peptidomimetic compounds[J].J Med Chem,2010,53(6):2502.

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通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142

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Progress on antifungal drug targets and inhibitors

1. School of Pharmacy, Second Military Medicinal University, Shanghai 200433, China;Chongming Substation, Shanghai Food and Drug Administration, Shanghai 202150, China

2. School of Pharmacy, Second Military Medicinal University, Shanghai 200433, China

Received Date: 2012-12-14

Rev Recd Date: 2013-04-08

Key words:

Abstract: Objective To review recent progress of antifungal drug targets and their inhibitors. Methods Literatures in recent five years were analyzed in combination of the authors'own research work and recent developments of antifungal targets and inhibitors were summarized. Results Current research focused on lanosterol 14-demethylase, β-1,3-glucan synthase, N-myristoyltransferase and secreted aspartic protease. The inhibitors of these targets showed promising future for the development of new antifungal drugs. Conclusion Optimizing the chemical structures of current antifungal agents and discover lead compounds with novel mode of action are of great importance to develop new generation of antifungal agents.

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Reference (29)

[1]	Brown GD,Denning DW,Levitz SM.Tackling human fungal infections[J].Science,2012,336(6082):647.
[2]	Lai CC,Tan CK,Huang YT,et al.Current challenges in the management of invasive fungal infections[J].J Infect Chemother,2008,14(2):77.
[3]	Park BJ,Wannemuehler KA,Marston BJ,et al.Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS[J].AIDS. 2009, 23(4):525.
[4]	Sheng C,Zhang W.New lead structures in antifungal drug discovery[J].Curr Med Chem.2011,18(5): 733.
[5]	Liu J,Balasubramanian MK.1,3-beta-Glucan synthase:a useful target for antifungal drugs[J].Curr Drug Targets Infect Disord.2001,1(2):159.
[6]	Kondoh O, Inagaki Y, Fukuda H,et al.Piperazine propanol derivative as a novel antifungal targeting 1,3-beta-D-glucan synthase[J].Biol Pharm Bull, 2005,28(11):2138.
[7]	Ting PC,Kuang R,Wu H,et al.The synthesis and structure-activity relationship of pyridazinones as glucan synthase inhibitors[J].Bioorg Med Chem Lett.2011,21(6):1819.
[8]	Zhou G,Ting PC,Aslanian R,et al.SAR studies of pyridazinone derivatives as novel glucan synthase inhibitors[J].Bioorg Med Chem Lett.2011,21(10):2890.
[9]	Guinea J,Recio S,Escribano P,et al.In vitro antifungal activities of isavuconazole and comparators against rare yeast pathogens[J].Antimicrob Agents Chemother.2010,54(9):4012.
[10]	Miller JL,Schell WA,Wills EA,et al.In vitro and in vivo efficacies of the new triazole albaconazole against Cryptococcus neoformans[J].Antimicrob Agents Chemother,2004,48(2):384.
[11]	Sheng C,Zhang W,Zhang M,et al.Homology modeling of lanosterol 14-demethylase of Candida albicans and Aspergillus fumigatus and insights into the enzyme-substrate interactions[J].J Biomol Struct & Dyn,2004,22(1):91.
[12]	Sheng C,Wang W,Che X,et al.Improved model of lanosterol 14alpha-demethylase by ligand-supported homology modeling: validation by virtual screening and azole optimization[J].Chem Med Chem,2010,5(3):390.
[13]	Sheng C,Miao Z,Ji H,et al.Three-dimensional model of lanosterol 14 alpha-demethylase from Cryptococcus neoformans: active-site characterization and insights into azole binding[J].Antimicrob Agents Chemother,2009,53(8):3487.
[14]	Sheng C,Che X,Wang W,et al.Design and synthesis of novel triazole antifungal derivatives by structure-based bioisosterism[J].Eur J Med Chem,2011,46(11):5276.
[15]	Sheng C,Che X,Wang W,et al.Structure-based design,synthesis,and antifungal activity of new triazole derivatives[J].Chem Biol Drug Des,2011,78(2):309.
[16]	Wang W,Wang S,Liu Y,et al.Novel conformationally restricted triazole derivatives with potent antifungal activity[J].Eur J Med Chem. 2010,45(2):6020.
[17]	Sun N,Wen J,Lu G,et al.An ultra-fast LC method for the determination of iodiconazole in microdialysis samples and its application in the calibration of laboratory-made linear probes[J].J Pharm Biomed Anal,2010,51(1):248.
[18]	Weston SA,Camble R,Colls J,et al.Crystal structure of the anti-fungal target N-myristoyl transferase[J].Nat Struct Biol,1998,5(3):213.
[19]	Sogabe S,Masubuchi M,Sakata K,et al.Crystal structures of Candida albicans N-myristoyltransferase with two distinct inhibitors[J].Chem Biol,2002,9(10):1119.
[20]	Farazi TA,Waksman G,Gordon JJ. The biology and enzymology of protein N-myristoyla[J].J Biol Chem,2001,276(43):39051.
[21]	Yamazaki K,Kaneko Y,Suwa K,et al.Synthesis of potent and selective inhibitors of Candida albicans N-myristoyltransferase based on the benzothiazole structure[J].J Biol Chem,2005,13(7):2509.
[22]	Ebara S,Naito H,Nakazawa K,et al.FTR1335 is a novel synthetic inhibitor of Candida albicans N-myristoyltransferase with fungicidal activity[J].Biol Pharm Bull,2005,28(4):591.
[23]	Sheng C,Zhu J,Zhang W,et al.3D-QSAR and molecular docking studies on benzothiazole derivatives as Candida albicans N-myristoyltransferase inhibitors[J].Eur J Med Chem,2007,42(4):477.
[24]	Sheng C,Xu H,Wang W,et al.Design, synthesis and antifungal activity of isosteric analogues of benzoheterocyclic N-myristoyltransferase Inhibitors[J].Eur J Med Chem,2010,45(9):3531.
[25]	盛春泉,张万年,王文雅,等. 取代四氢咔唑类抗真菌化合物及其制备方法[P].中国专利,201110094585.4,2011-04-15.
[26]	Cutfield SM,Dodson EJ,Anderson BF,et al.The crystal structure of a major secreted aspartic proteinase from Candida albicans in complexes with two inhibitors[J].Structure,1995,3(11):1261.
[27]	Stewart K,Abad-Zapatero C.Candida proteases and their inhibition: prospects for antifungal therapy[J].Curr Med Chem,2001,8(8):941.[JP2]
[28]	Degel B,Staib P,Rohrer S,et al.Cis-Configured aziridines are new pseudo-irreversible dual-mode inhibitors of Candida albicans secreted aspartic protease 2[J].Chem Med Chem 2008,3(2):302.
[29]	Trabocchi A,Mannino C,Machetti F,et al.Identification of inhibitors of drug-resistant Candida albicans strains from a library of bicyclic peptidomimetic compounds[J].J Med Chem,2010,53(6):2502.

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Progress on antifungal drug targets and inhibitors

doi: 10.3969/j.issn.1006-0111.2013.05.001

Abstract

References

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通讯作者: 陈斌, bchen63@163.com

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