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. 1996 Apr;40(4):1044–1047. doi: 10.1128/aac.40.4.1044

Inhibition of 2,3-oxidosqualene-lanosterol cyclase in Candida albicans by pyridinium ion-based inhibitors.

R C Goldman 1, D Zakula 1, J O Capobianco 1, B A Sharpe 1, J H Griffin 1
PMCID: PMC163259  PMID: 8849227

Abstract

The N-(4E,8E)-5,9,13-trimethyl-4,8,12-tetradecatrien-1- ylpyridinium and N-(4E,8E)-5,9,13-trimethyl-4,8,12-tetradecatrien-1- ylpicolinium cations were evaluated for their ability to inhibit 2,3-oxidosqualene-lanosterol cyclase activity in Candida albicans. Both compounds inhibited fungal growth, were fungicidal, and resulted in the accumulation of squalene epoxide concurrent with a decrease in ergosterol, monomethyl sterols, and lanosterol, as was expected for the specific inhibition of 2,3-oxidosqualene-lanosterol cyclase activity. These compounds are electron-poor aromatic mimics of a monocyclized transition state or high-energy intermediate formed from oxidosqualene, which may explain their selective action.

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Selected References

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  1. Abe I., Bai M., Xiao X. Y., Prestwich G. D. Affinity labeling of vertebrate oxidosqualene cyclases with a tritiated suicide substrate. Biochem Biophys Res Commun. 1992 Aug 31;187(1):32–38. doi: 10.1016/s0006-291x(05)81454-8. [DOI] [PubMed] [Google Scholar]
  2. Abe I., Prestwich G. D. Active site mapping of affinity-labeled rat oxidosqualene cyclase. J Biol Chem. 1994 Jan 14;269(2):802–804. [PubMed] [Google Scholar]
  3. Balliano G., Grosa G., Milla P., Viola F., Cattel L. 3-Carboxy-4-nitrophenyl-dithio-1,1',2-trisnorsqualene: a site-directed inactivator of yeast oxidosqualene cyclase. Lipids. 1993 Oct;28(10):903–906. doi: 10.1007/BF02537498. [DOI] [PubMed] [Google Scholar]
  4. Balliano G., Milla P., Ceruti M., Carrano L., Viola F., Brusa P., Cattel L. Inhibition of sterol biosynthesis in Saccharomyces cerevisiae and Candida albicans by 22,23-epoxy-2-aza-2,3-dihydrosqualene and the corresponding N-oxide. Antimicrob Agents Chemother. 1994 Sep;38(9):1904–1908. doi: 10.1128/aac.38.9.1904. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Balliano G., Milla P., Ceruti M., Viola F., Carrano L., Cattel L. Differential inhibition of fungal oxidosqualene cyclase by 6E and 6Z isomers of 2,3-epoxy-10-aza-10,11-dihydrosqualene. FEBS Lett. 1993 Apr 12;320(3):203–206. doi: 10.1016/0014-5793(93)80586-j. [DOI] [PubMed] [Google Scholar]
  6. Balliano G., Viola F., Cattel L. Inhibitors of ergosterol biosynthesis as potential antifungal drugs. Ital J Biochem. 1989 Jul-Aug;38(4):299A–300A. [PubMed] [Google Scholar]
  7. Balliano G., Viola F., Ceruti M., Cattel L. Inhibition of sterol biosynthesis in Saccharomyces cerevisiae by N,N-diethylazasqualene and derivatives. Biochim Biophys Acta. 1988 Mar 4;959(1):9–19. doi: 10.1016/0005-2760(88)90144-0. [DOI] [PubMed] [Google Scholar]
  8. Capobianco J. O., Doran C. C., Goldman R. C., De B. A non-azole inhibitor of lanosterol 14 alpha-methyl demethylase in Candida albicans. J Antimicrob Chemother. 1992 Dec;30(6):781–790. doi: 10.1093/jac/30.6.781. [DOI] [PubMed] [Google Scholar]
  9. Cattel L., Ceruti M., Balliano G., Viola F., Grosa G., Schuber F. Drug design based on biosynthetic studies: synthesis, biological activity, and kinetics of new inhibitors of 2,3-oxidosqualene cyclase and squalene epoxidase. Steroids. 1989 Mar-May;53(3-5):363–391. doi: 10.1016/0039-128x(89)90020-2. [DOI] [PubMed] [Google Scholar]
  10. Cattel L., Ceruti M., Viola F., Delprino L., Balliano G., Duriatti A., Bouvier-Navé P. The squalene-2,3-epoxide cyclase as a model for the development of new drugs. Lipids. 1986 Jan;21(1):31–38. doi: 10.1007/BF02534300. [DOI] [PubMed] [Google Scholar]
  11. Corey E. J., Matsuda S. P., Bartel B. Molecular cloning, characterization, and overexpression of ERG7, the Saccharomyces cerevisiae gene encoding lanosterol synthase. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2211–2215. doi: 10.1073/pnas.91.6.2211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Georgopapadakou N. H., Dix B. A., Smith S. A., Freudenberger J., Funke P. T. Effect of antifungal agents on lipid biosynthesis and membrane integrity in Candida albicans. Antimicrob Agents Chemother. 1987 Jan;31(1):46–51. doi: 10.1128/aac.31.1.46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jolidon S., Polak A. M., Guerry P., Hartman P. G. Inhibitors of 2,3-oxidosqualene lanosterol-cyclase as potential antifungal agents. Biochem Soc Trans. 1990 Feb;18(1):47–48. doi: 10.1042/bst0180047. [DOI] [PubMed] [Google Scholar]
  14. Kelly R., Miller S. M., Lai M. H., Kirsch D. R. Cloning and characterization of the 2,3-oxidosqualene cyclase-coding gene of Candida albicans. Gene. 1990 Mar 15;87(2):177–183. doi: 10.1016/0378-1119(90)90299-7. [DOI] [PubMed] [Google Scholar]
  15. Lees N. D., Skaggs B., Kirsch D. R., Bard M. Cloning of the late genes in the ergosterol biosynthetic pathway of Saccharomyces cerevisiae--a review. Lipids. 1995 Mar;30(3):221–226. doi: 10.1007/BF02537824. [DOI] [PubMed] [Google Scholar]
  16. Ryder N. S. Squalene epoxidase as a target for the allylamines. Biochem Soc Trans. 1991 Aug;19(3):774–777. doi: 10.1042/bst0190774. [DOI] [PubMed] [Google Scholar]
  17. Ryder N. S. Terbinafine: mode of action and properties of the squalene epoxidase inhibition. Br J Dermatol. 1992 Feb;126 (Suppl 39):2–7. doi: 10.1111/j.1365-2133.1992.tb00001.x. [DOI] [PubMed] [Google Scholar]
  18. Shi Z., Buntel C. J., Griffin J. H. Isolation and characterization of the gene encoding 2,3-oxidosqualene-lanosterol cyclase from Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7370–7374. doi: 10.1073/pnas.91.15.7370. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Vanden Bossche H., Marichal P., Gorrens J., Coene M. C. Biochemical basis for the activity and selectivity of oral antifungal drugs. Br J Clin Pract Suppl. 1990 Sep;71:41–46. [PubMed] [Google Scholar]
  20. Vanden Bossche H., Marichal P., Gorrens J., Coene M. C., Willemsens G., Bellens D., Roels I., Moereels H., Janssen P. A. Biochemical approaches to selective antifungal activity. Focus on azole antifungals. Mycoses. 1989;32 (Suppl 1):35–52. doi: 10.1111/j.1439-0507.1989.tb02293.x. [DOI] [PubMed] [Google Scholar]

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