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Design of potent selective zinc-mediated serine protease inhibitors

Nature volume 391, pages 608–612 (1998)Cite this article

Abstract

Many serine proteases are targets for therapeutic intervention because they often play key roles in disease1. Small molecule inhibitors of serine proteases with high affinity are especially interesting as they could be used as scaffolds from which to develop drugs selective for protease targets. One such inhibitor is bis(5-amidino-2-benzimidazolyl)methane (BABIM), standing out as the best inhibitor of trypsin (by a factor of over 100) in a series of over 60 relatively closely related analogues2,3,4. By probing the structural basis of inhibition, we discovered, using crystallographic methods, a new mode of high-affinity binding in which a Zn2+ ion is tetrahedrally coordinated between two chelating nitrogens of BABIM and two active site residues, His 57 and Ser 195. Zn2+, at subphysiological levels, enhances inhibition by over 103-fold. The distinct Zn2+ coordination geometry implies a strong dependence of affinity on substituents. This unique structural paradigm has enabled development of potent, highly selective, Zn2+-dependent inhibitors of several therapeutically important serine proteases, using a physiologically ubiquitous metal ion.

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Figure 1
Figure 2: Superposition of trypsin-BABIM-Zn2+ onto keto-BABIM-Zn2+.
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Acknowledgements

We thank K. Spear for synthesis of BABIM, T. Church and M. Linsell for synthesis of Arris compounds, L. Cregar, D. Putnam and R. Warne for enzyme assays, and M. Venuti for review and discussion of the manuscript.

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Author notes

  1. Thomas E. Jenkins

    Present address: Advanced Medicine Inc., 270B Littlefield Avenue, South San Francisco, California, 94080, USA

Authors and Affiliations

  1. Arris Pharmaceutical Corporation, 385 Oyster Point Boulevard, Suite 3, South San Francisco, 94080, California, USA

    Bradley A. Katz, James M. Clark, Charles R. Johnson, Michael J. Ross, Christine Luong, William R. Moore & Robert M. Stroud

  2. Department of Biochemistry, University of California at San Francisco, California, 94143, USA

    Janet S. Finer-Moore & Robert M. Stroud

Authors
  1. Bradley A. Katz
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  2. James M. Clark
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Correspondence to Bradley A. Katz.

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Katz, B., Clark, J., Finer-Moore, J. et al. Design of potent selective zinc-mediated serine protease inhibitors. Nature 391, 608–612 (1998). https://doi.org/10.1038/35422

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