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Research ArticleDrug Discovery and Translational Medicine

Structure-Based Optimization of Angiostatic Agent 6DBF7, an Allosteric Antagonist of Galectin-1

Ruud P. M. Dings, Nigam Kumar, Michelle C. Miller, Melissa Loren, Huzaifa Rangwala, Thomas R. Hoye and Kevin H. Mayo
Journal of Pharmacology and Experimental Therapeutics March 2013, 344 (3) 589-599; DOI: https://doi.org/10.1124/jpet.112.199646
Ruud P. M. Dings
Departments of Biochemistry, Molecular Biology & Biophysics (R.P.M.D., N.K., M.C.M., M.L., K.H.M.), and Chemistry (H.R., T.R.H.), University of Minnesota, Minneapolis, Minnesota
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Nigam Kumar
Departments of Biochemistry, Molecular Biology & Biophysics (R.P.M.D., N.K., M.C.M., M.L., K.H.M.), and Chemistry (H.R., T.R.H.), University of Minnesota, Minneapolis, Minnesota
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Michelle C. Miller
Departments of Biochemistry, Molecular Biology & Biophysics (R.P.M.D., N.K., M.C.M., M.L., K.H.M.), and Chemistry (H.R., T.R.H.), University of Minnesota, Minneapolis, Minnesota
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Melissa Loren
Departments of Biochemistry, Molecular Biology & Biophysics (R.P.M.D., N.K., M.C.M., M.L., K.H.M.), and Chemistry (H.R., T.R.H.), University of Minnesota, Minneapolis, Minnesota
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Huzaifa Rangwala
Departments of Biochemistry, Molecular Biology & Biophysics (R.P.M.D., N.K., M.C.M., M.L., K.H.M.), and Chemistry (H.R., T.R.H.), University of Minnesota, Minneapolis, Minnesota
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Thomas R. Hoye
Departments of Biochemistry, Molecular Biology & Biophysics (R.P.M.D., N.K., M.C.M., M.L., K.H.M.), and Chemistry (H.R., T.R.H.), University of Minnesota, Minneapolis, Minnesota
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Kevin H. Mayo
Departments of Biochemistry, Molecular Biology & Biophysics (R.P.M.D., N.K., M.C.M., M.L., K.H.M.), and Chemistry (H.R., T.R.H.), University of Minnesota, Minneapolis, Minnesota
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Abstract

Galectin-1 (gal-1), which binds β-galactoside groups on various cell surface receptors, is crucial to cell adhesion and migration, and is found to be elevated in several cancers. Previously, we reported on 6DBF7, a dibenzofuran (DBF)-based peptidomimetic of the gal-1 antagonist anginex. In the present study, we used a structure-based approach to optimize 6DBF7. Initial NMR studies showed that 6DBF7 binds to gal-1 on one side of the β-sandwich away from the lectin’s carbohydrate binding site. Although an alanine scan of 6DBF7 showed that the two cationic groups (lysines) in the partial peptide are crucial to its angiostatic activity, it is the hydrophobic face of the amphipath that appears to interact directly with the surface of gal-1. Based on this structural information, we designed and tested additional DBF analogs. In particular, substitution of the C-terminal Asp for alanine and branched alkyl side chains (Val, Leu, Ile) for linear ones (Nle, Nva) rendered the greatest improvements in activity. Flow cytometry with gal-1−/− splenocytes showed that 6DBF7 and two of its more potent analogs (DB16 and DB21) can fully inhibit fluorescein isothiocyanate–gal-1 binding. Moreover, heteronuclear single-quantum coherence NMR titrations showed that the presence of DB16 decreases gal-1 affinity for lactose, indicating that the peptidomimetic targets gal-1 as a noncompetitive, allosteric inhibitor of glycan binding. Using tumor mouse models (B16F10 melanoma, LS174 lung, and MA148 ovarian), we found that DB21 inhibits tumor angiogenesis and tumor growth significantly better than 6DBF7, DB16, or anginex. DB21 is currently being developed further and holds promise for the management of human cancer in the clinic.

Footnotes

  • This work was supported by a research grant from the National Institutes of Health National Cancer Institute [Grant R01 CA-096090] to K.H.M.

  • dx.doi.org/10.1124/jpet.112.199646.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Received August 27, 2012.
  • Accepted December 10, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 344 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 344, Issue 3
1 Mar 2013
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Research ArticleDrug Discovery and Translational Medicine

Optimizing DBF-Anginex Mimetics

Ruud P. M. Dings, Nigam Kumar, Michelle C. Miller, Melissa Loren, Huzaifa Rangwala, Thomas R. Hoye and Kevin H. Mayo
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 589-599; DOI: https://doi.org/10.1124/jpet.112.199646

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Research ArticleDrug Discovery and Translational Medicine

Optimizing DBF-Anginex Mimetics

Ruud P. M. Dings, Nigam Kumar, Michelle C. Miller, Melissa Loren, Huzaifa Rangwala, Thomas R. Hoye and Kevin H. Mayo
Journal of Pharmacology and Experimental Therapeutics March 1, 2013, 344 (3) 589-599; DOI: https://doi.org/10.1124/jpet.112.199646
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