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Leeyuan Huang,
Russell B. Lingham,
Guy H. Harris,
Sheo B. Singh,
Claude Dufresne,
Mary Nallin-Omstead,
Gerald F. Bills,
Marina Mojena, Manuel Sanchez,
John D. Karkas,
Jackson B. Gibbs,
Wendy H. Clapp,
Maria S. Meinz,
Keith C. Silverman,
James D. Bergstrom
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ABSTRACT: Several potent inhibitors of squalence synthetase have been discovered. Zaragozic acid A is produced by several fungi; zaragozic acid B is produced by several strains of Sporormiella intermedia; zaragozic acids C, E, and F are produced by Leptodontidium elatius; zaragozic acids D and D2 are produced by Amauroascus niger. L-731,120 and L-731,128 are minor components and coproduced with zaragozic acids A and B, respectively. Viridiofungins A, B, and C are produced by Trichoderma viride. Viridiofungin A is also produced by an unidentified sterile fungus. Several of the zaragozic acids are also potent inhibitors of farnesyl-protein transferase (FPTase). Inhibitors of FPTase may act as potential anticancer drugs. Chaetomellic acids A and B are produced by a fungus, Chaetomella acutiseta, while fusidienol is produced by Fusidium griseum. All three compounds are potent inhibitors of FPTase. Our experiences suggest that many novel inhibitors of both squalene synthase and FPTase are produced within a diverse phylogenetic array of filamentous fungi. Several of the zaragozic acids are potent inhibitors of both FPTase and squalene synthases. This is consistent with our observations that zaragozic acids and chaetomellic acids share some structural similarity. Key words: natural inhibitors, squalene synthase, farnesyl-protein transferase.
Canadian Journal of Botany 03/2011; 73:898-906. · 1.40 Impact Factor
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Sheo B Singh,
John G Ondeyka,
Nasios Tsipouras,
Carolyn Ruby,
Vinod Sardana,
Marvin Schulman, Manuel Sanchez,
Fernando Pelaez,
Mark W Stahlhut,
Sanjeev Munshi,
David B Olsen,
Russell B Lingham
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ABSTRACT: HIV-1 protease is one of several key enzymes required for the replication and maturation of HIV-1 virus. An almost two-decade research effort by academic and pharmaceutical institutions resulted in the successful commercialization of seven drugs that are potent inhibitors of HIV-1 protease activity and which, if used correctly, are highly effective in managing viral load. However, identification of clinical viral isolates that are resistant to these drugs indicates that this is a significant problem and that new classes of inhibitors are continually needed. Screening of microbial extracts followed by bioassay-guided isolation led to the discovery of a natural hinnuliquinone, a C(2)-symmetric bis-indolyl quinone natural product that inhibited the wild-type and a clinically resistant (A44) strain of HIV-1 protease with K(i) values of 0.97 and 1.25microM, respectively. Crystallographic analysis of the inhibitor-bound HIV-1 protease helped explain the importance of the C(2)-symmetry of hinnuliquinone for activity. Details of the isolation, biological activity, and crystallographic analysis of the inhibitor-bound protease are herein described.
Biochemical and Biophysical Research Communications 12/2004; 324(1):108-13. · 2.48 Impact Factor
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Hiranthi Jayasuriya,
Kithsiri B Herath,
John G Ondeyka,
Jon D Polishook,
Gerald F Bills,
Anne W Dombrowski,
Marty S Springer,
Sal Siciliano,
Lorraine Malkowitz, Manuel Sanchez,
Ziqiang Guan,
Suroojnauth Tiwari,
Dennis W Stevenson,
Robert P Borris,
Sheo B Singh
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ABSTRACT: Human CCR5 is a G-coupled receptor that binds to the envelope protein gp120 and CD4 and mediates the HIV-1 viral entry into the cells. The blockade of this binding by a small molecule receptor antagonist could lead to a new mode of action agent for HIV-1 and AIDS. Screening of natural product extracts led to the identification of anibamine (1), a novel pyridine quaternary alkaloid as a TFA salt, from Aniba sp.; ophiobolin C from fermentation extracts of fungi Mollisia sp.; and 19,20-epoxycytochalasin Q from Xylaria sp. Formation of the TFA salt of anibamine is plausibly an artifact of the isolation. The identity of the natural counterion is unknown. Anibamine.TFA competed for the binding of 125I-gp120 to human CCR5 with an IC50 of 1 microM. Ophiobolin C and 19,20-epoxycytochalasin Q exhibited binding IC50) values of 40 and 60 microM, respectively.
Journal of Natural Products 07/2004; 67(6):1036-8. · 3.13 Impact Factor
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The Journal of Organic Chemistry 11/1997; 62(21):7485-7488. · 4.45 Impact Factor
