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The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites

Nature Structural Biology volume 9, pages 57–60 (2002)Cite this article

Abstract

Cryptolepine, a naturally occurring indoloquinoline alkaloid used as an antimalarial drug in Central and Western Africa, has been found to bind to DNA in a formerly unknown intercalation mode. Evidence from competition dialysis assays demonstrates that cryptolepine is able to bind CG-rich sequences containing nonalternating CC sites. Here we show that cryptolepine interacts with the CC sites of the DNA fragment d(CCTAGG)2 in a base-stacking intercalation mode. This is the first DNA intercalator complex, from ∼90 solved by X-ray crystallography, to bind a nonalternating (pyrimidine-pyrimidine) DNA sequence. The asymmetry of the drug induces a perfect stacking with the asymmetric site, allowing for the stability of the complex in the absence of hydrogen bonding interactions. The crystal structure of this antimalarial drug–DNA complex provides evidence for the first nonalternating intercalation and, as such, provides a basis for the design of new anticancer or antimalarial drugs.

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Figure 1: Diagram showing the main intercalation modes.
Figure 2: Results obtained from the Ren and Chaires competition dialysis experiment for cryptolepine.
Figure 3: Crystal structure of the complex.

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Acknowledgements

This work was supported by grants from the Ministerio de Educacion y Cultura of Spain and the Generalitat de Catalunya. J.N.L. acknowledges support from MEyC of Spain. Synchrotron data collection was supported by the ESRF and EU grants to the EMBL-DESY.

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Authors and Affiliations

  1. Institut de Biologia Molecular de Barcelona, C.S.I.C., Jordi Girona 18, Barcelona, 08034, Spain

    John N. Lisgarten, Miquel Coll, Jose Portugal & Juan Aymami

  2. Department of Crystallography, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK

    John N. Lisgarten

  3. The School of Pharmacy, University of Bradford, West Yorkshire, BD7 4ER, UK

    Colin W. Wright

  4. Department d'Enginyeria Quimica, Universitat Politècnica de Catalunya, Diagonal 647, Barcelona, 08028, Spain

    Juan Aymami

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  1. John N. Lisgarten
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Correspondence to Juan Aymami.

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Lisgarten, J., Coll, M., Portugal, J. et al. The antimalarial and cytotoxic drug cryptolepine intercalates into DNA at cytosine-cytosine sites. Nat Struct Mol Biol 9, 57–60 (2002). https://doi.org/10.1038/nsb729

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