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Engineering strategy to improve peptide analogs: from structure-based computational design to tumor homing
Zanuy Gomara, David; Sayago García, Francisco Javier; Revilla López, Guillermo; Ballano Ballano, María Gema; Agemy, Lilach; Kotamraju, Venkata Ramana; Jimenez, Ana I.; Cativiela, Carlos; Nussinov, Ruth; Sawvel, April M.; Ruoslahti, Erkki; Stucky, Galen; Alemán Llansó, Carlos
Universitat Politècnica de Catalunya. Departament d'Enginyeria Química; Universitat Politècnica de Catalunya. IMEM - Innovació, Modelització i Enginyeria en (BIO) Materials
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 mod- eling using a combination of simulated annealing and molecular dynamics were carried out to design targeted replacements aimed at enhancing the stability of the bio- active conformation of CREKA. Because this conforma- tion presents a pocket-like shape with the charged groups of Arg, Glu and Lys pointing outward, non-proteinogenic amino acids a -methyl and N -methyl derivatives of Arg, Glu and Lys were selected, rationally designed and incor- porated 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 stabil- ization. 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 con- verge and lead to useful biomedical advances
Peer Reviewed
Àrees temàtiques de la UPC::Enginyeria química
Peptides--Synthesis
Computational design
Bioactive conformation dynamics
Tumor-homing
peptide
Peptide synthesis
Tumor growth inhibitors
ALPHA-AMINO-ACIDS
SOLID-PHASE SYNTHESIS
STEREOSELECTIVE-SYNTHESIS
RECEPTOR ANTAGONISTS
MOLECULAR-DYNAMICS
HIGHLY POTENT
INHIBITORS
PENTAPEPTIDE
CONFORMATION
SIMULATION
Pèptids -- Síntesi
Attribution-NonCommercial-NoDerivs 3.0 Spain
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/publishedVersion
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