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: 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
• Journal: Journal of computer-aided molecular design (J Comput Aided Mol Des) Vol. 27 Issue 1 Pg. 31-43 (Jan 2013) ISSN: 1573-4951 [Electronic] Netherlands
• PMID: 23239171 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Amino Acids
• Antineoplastic Agents
• Oligopeptides
• Peptides
• cysteinyl-arginyl-glutamyl-lysyl-alanyl

Topics

• Amino Acids (chemical synthesis)
• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Drug Design
• Drug Screening Assays, Antitumor (methods)
• Mice
• Molecular Dynamics Simulation
• Nanostructures (chemistry)
• Oligopeptides (chemistry, metabolism, pharmacology)
• Peptides (chemistry)
• Protein Conformation