title: Engineering strategy to improve peptide analogs: from structure-based computational design to tumor homing.
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.
authors.affiliation: Department of Chemical Engineering, ETSEIB, Universitat Politècnica de Catalunya, Diagonal 647, 08028 Barcelona, Spain. david.zanuy@upc.edu
authors.forename: David
authors.initials: D
authors.lastname: Zanuy
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Sayago
authors.forename: Guillem
authors.initials: G
authors.lastname: Revilla-López
authors.forename: Gema
authors.initials: G
authors.lastname: Ballano
authors.forename: Lilach
authors.initials: L
authors.lastname: Agemy
authors.forename: Venkata Ramana
authors.initials: VR
authors.lastname: Kotamraju
authors.forename: Ana I
authors.initials: AI
authors.lastname: Jiménez
authors.forename: Carlos
authors.initials: C
authors.lastname: Cativiela
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
authors.forename: April M
authors.initials: AM
authors.lastname: Sawvel
authors.forename: Galen
authors.initials: G
authors.lastname: Stucky
authors.forename: Erkki
authors.initials: E
authors.lastname: Ruoslahti
authors.forename: Carlos
authors.initials: C
authors.lastname: Alemán
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D051379:Mice; D056004:Molecular Dynamics Simulation; D049329:Nanostructures / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation
chemical_list: D000596:Amino Acids; D000970:Antineoplastic Agents; D009842:Oligopeptides; D010455:Peptides; C542438:cysteinyl-arginyl-glutamyl-lysyl-alanyl