Article

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 ZanuyAffiliated withDepartment of Chemical Engineering, ETSEIB, Universitat Politècnica de Catalunya Email author 
  • , Francisco J. SayagoAffiliated withDepartment of Organic Chemistry, ISQCH, University of Zaragoza-CSIC
  • , Guillem Revilla-LópezAffiliated withDepartment of Chemical Engineering, ETSEIB, Universitat Politècnica de Catalunya
  • , Gema BallanoAffiliated withDepartment of Organic Chemistry, ISQCH, University of Zaragoza-CSIC
  • , Lilach AgemyAffiliated withCenter for Nanomedicine, Sanford-Burnham Medical Research Institute, Burnham Institute for Medical Research at UCSB, University of California
  • , Venkata Ramana KotamrajuAffiliated withCenter for Nanomedicine, Sanford-Burnham Medical Research Institute, Burnham Institute for Medical Research at UCSB, University of California
  • , Ana I. JiménezAffiliated withDepartment of Organic Chemistry, ISQCH, University of Zaragoza-CSIC
  • , Carlos CativielaAffiliated withDepartment of Organic Chemistry, ISQCH, University of Zaragoza-CSIC
  • , Ruth NussinovAffiliated withBasic Science Program, Center for Cancer Research Nanobiology Program, SAIC-Frederick, Inc., NCIDepartment of Human Genetics, Sackler, Medical School, Tel Aviv University
    • , April M. SawvelAffiliated withDepartment of Chemistry and Biochemistry, University of California
    • , Galen StuckyAffiliated withDepartment of Chemistry and Biochemistry, University of California
    • , Erkki RuoslahtiAffiliated withCenter for Nanomedicine, Sanford-Burnham Medical Research Institute, Burnham Institute for Medical Research at UCSB, University of CaliforniaCancer Center, Sanford-Burnham Medical Research Institute
    • , Carlos AlemánAffiliated withDepartment of Chemical Engineering, ETSEIB, Universitat Politècnica de CatalunyaCenter for Research in Nano-Engineering, Universitat Politècnica de Catalunya Email author 

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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