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PEDS Advance Access published online on February 28, 2008
Protein Engineering Design and Selection, doi:10.1093/protein/gzm089
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Article

Genetic selection for peptide inhibitors of angiogenin

Bryan D. Smith1,3 and Ronald T. Raines1,2,4

1Department of Biochemistry, University of Wisconsin–Madison, 433 Babcock Drive, Madison, WI 53706-1544 2Department of Chemistry, University of Wisconsin–Madison, 1101 University Avenue, Madison, WI 53706-1322, USA

4 To whom correspondence should be addressed. E-mail: rtraines{at}wisc.edu

The improper regulation of angiogenesis is implicit in a variety of diseases, including cancer. Angiogenin is unique among angiogenic factors in having ribonucleolytic activity. Inhibitors of this activity could serve as chemotherapeutics. The ribonucleolytic activity of angiogenin is toxic to the OrigamiTM strain of Escherichia coli. Herein, this cytotoxicity was used to identify inhibitors from a random nonapeptide library tethered to the C-terminus of human angiogenin. The selected sequences fell into three classes: (i) extremely hydrophobic, (ii) putative protease (ClpXP) substrates and (iii) slightly anionic. Two peptides corresponding to sequences in the last class were synthesized chemically and found to inhibit the ribonucleolytic activity of human angiogenin in vitro with micromolar values of Ki. Both peptides also inhibit bovine pancreatic ribonuclease, a homolog of angiogenin, though one exhibits selectivity for angiogenin. The affinity and selectivity of these peptides are comparable with the best known inhibitors of angiogenin. Moreover, the strategy used to identify them is general and could be applied to other cytotoxins.

Keywords: cytotoxin/genetic selection/inhibitor/peptide/ribonuclease

Received September 12, 2007; revised November 17, 2007; accepted December 11, 2007.

3 Present address: Deciphera Pharmaceuticals LLC, 4950 Research Park Way, Lawrence, KS 66047, USA


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