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

  • David Zanuy
  • Francisco J. Sayago
  • Guillem Revilla-López
  • Gema Ballano
  • Lilach Agemy
  • Venkata Ramana Kotamraju
  • Ana I. Jiménez
  • Carlos Cativiela
  • Ruth Nussinov
  • April M. Sawvel
  • Galen Stucky
  • Erkki Ruoslahti
  • Carlos Alemán
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 designBioactive conformation dynamicsTumor-homing peptidePeptide synthesisTumor 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

Authors and Affiliations

  • David Zanuy
    • 1
  • Francisco J. Sayago
    • 2
  • Guillem Revilla-López
    • 1
  • Gema Ballano
    • 2
  • Lilach Agemy
    • 3
  • Venkata Ramana Kotamraju
    • 3
  • Ana I. Jiménez
    • 2
  • Carlos Cativiela
    • 2
  • Ruth Nussinov
    • 4
    • 5
  • April M. Sawvel
    • 6
  • Galen Stucky
    • 6
  • Erkki Ruoslahti
    • 3
    • 7
  • Carlos Alemán
    • 1
    • 8
  1. 1.Department of Chemical EngineeringETSEIB, Universitat Politècnica de CatalunyaBarcelonaSpain
  2. 2.Department of Organic ChemistryISQCH, University of Zaragoza-CSICZaragozaSpain
  3. 3.Center for Nanomedicine, Sanford-Burnham Medical Research Institute, Burnham Institute for Medical Research at UCSBUniversity of CaliforniaSanta BarbaraUSA
  4. 4.Basic Science Program, Center for Cancer Research Nanobiology ProgramSAIC-Frederick, Inc., NCIFrederickUSA
  5. 5.Department of Human Genetics, Sackler, Medical SchoolTel Aviv UniversityTel AvivIsrael
  6. 6.Department of Chemistry and BiochemistryUniversity of CaliforniaSanta BarbaraUSA
  7. 7.Cancer Center, Sanford-Burnham Medical Research InstituteLa JollaUSA
  8. 8.Center for Research in Nano-EngineeringUniversitat Politècnica de CatalunyaBarcelonaSpain