Journal of Computer-Aided Molecular Design

, Volume 27, Issue 1, pp 31–43

Engineering strategy to improve peptide analogs: from structure-based computational design to tumor homing

Authors

    • Department of Chemical EngineeringETSEIB, Universitat Politècnica de Catalunya
  • Francisco J. Sayago
    • Department of Organic ChemistryISQCH, University of Zaragoza-CSIC
  • Guillem Revilla-López
    • Department of Chemical EngineeringETSEIB, Universitat Politècnica de Catalunya
  • Gema Ballano
    • Department of Organic ChemistryISQCH, University of Zaragoza-CSIC
  • Lilach Agemy
    • Center for Nanomedicine, Sanford-Burnham Medical Research Institute, Burnham Institute for Medical Research at UCSBUniversity of California
  • Venkata Ramana Kotamraju
    • Center for Nanomedicine, Sanford-Burnham Medical Research Institute, Burnham Institute for Medical Research at UCSBUniversity of California
  • Ana I. Jiménez
    • Department of Organic ChemistryISQCH, University of Zaragoza-CSIC
  • Carlos Cativiela
    • Department of Organic ChemistryISQCH, University of Zaragoza-CSIC
  • Ruth Nussinov
    • Basic Science Program, Center for Cancer Research Nanobiology ProgramSAIC-Frederick, Inc., NCI
    • Department of Human Genetics, Sackler, Medical SchoolTel Aviv University
  • April M. Sawvel
    • Department of Chemistry and BiochemistryUniversity of California
  • Galen Stucky
    • Department of Chemistry and BiochemistryUniversity of California
  • Erkki Ruoslahti
    • Center for Nanomedicine, Sanford-Burnham Medical Research Institute, Burnham Institute for Medical Research at UCSBUniversity of California
    • Cancer Center, Sanford-Burnham Medical Research Institute
    • Department of Chemical EngineeringETSEIB, Universitat Politècnica de Catalunya
    • Center for Research in Nano-EngineeringUniversitat Politècnica de Catalunya
Article

DOI: 10.1007/s10822-012-9623-5

Cite this article as:
Zanuy, D., Sayago, F.J., Revilla-López, G. et al. J Comput Aided Mol Des (2013) 27: 31. doi:10.1007/s10822-012-9623-5

Abstract

We present a chemical strategy to engineer analogs of the tumor-homing peptide CREKA (Cys-Arg-Glu-Lys-Ala), which binds to fibrin and fibrin-associated clotted plasma proteins in tumor vessels (Simberg et al. in Proc Natl Acad Sci USA 104:932–936, 2007) with improved ability to inhibit tumor growth. Computer modeling using a combination of simulated annealing and molecular dynamics were carried out to design targeted replacements aimed at enhancing the stability of the bioactive conformation of CREKA. Because this conformation presents a pocket-like shape with the charged groups of Arg, Glu and Lys pointing outward, non-proteinogenic amino acids α-methyl and N-methyl derivatives of Arg, Glu and Lys were selected, rationally designed and incorporated into CREKA analogs. The stabilization of the bioactive conformation predicted by the modeling for the different CREKA analogs matched the tumor fluorescence results, with tumor accumulation increasing with stabilization. Here we report the modeling, synthetic procedures, and new biological assays used to test the efficacy and utility of the analogs. Combined, our results show how studies based on multi-disciplinary collaboration can converge and lead to useful biomedical advances.

Keywords

Computational design Bioactive conformation dynamics Tumor-homing peptide Peptide synthesis Tumor growth inhibitors

Supplementary material

10822_2012_9623_MOESM1_ESM.doc (2.3 mb)
Supplementary material 1 (DOC 2,324 kb)

Copyright information

© Springer Science+Business Media Dordrecht 2012