TY - JOUR
T1 - Engineering strategy to improve peptide analogs
T2 - From structure-based computational design to tumor homing
AU - Zanuy, David
AU - Sayago, Francisco J.
AU - Revilla-López, Guillem
AU - Ballano, Gema
AU - Agemy, Lilach
AU - Kotamraju, Venkata Ramana
AU - Jiménez, Ana I.
AU - Cativiela, Carlos
AU - Nussinov, Ruth
AU - Sawvel, April M.
AU - Stucky, Galen
AU - Ruoslahti, Erkki
AU - Alemán, Carlos
N1 - Funding Information:
Acknowledgments Computer resources were generously provided by the Centre de Supercomputació de Catalunya (CESCA), the Barcelona Supercomputing Center–Centro Nacional de Supecomputación (BSC–CNS), the National Cancer Institute for partial allocation of computing time and staff support at the Advanced Biomedical Computing Center of the Frederick Cancer Research and Development Center and the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov). This project has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the view of the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The work developed by the Spanish groups has been supported by MICINN and FEDER (MAT2009-09138 and CTQ2010-17436), by the Generalitat de Ca-talunya (research group 2009 SGR 925 and XRQTC), and Gobierno de Aragon-FSE (research group E-40). Support for the research of C.A. was received through the prize ‘‘ICREA Academia’’ for excellence in research funded by the Generalitat de Catalunya. Research in the Ru-oslahti laboratory is supported by grants from the NIH/NCI 5 P30 CA30199-28, awarded to the Sanford-Burnham Medical Research Institute, Cancer Center, and a DOD/CDMRP grant W81XWH-10-1-0199.
PY - 2013/1
Y1 - 2013/1
N2 - 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.
AB - 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.
KW - Bioactive conformation dynamics
KW - Computational design
KW - Peptide synthesis
KW - Tumor growth inhibitors
KW - Tumor-homing peptide
UR - http://www.scopus.com/inward/record.url?scp=84874109414&partnerID=8YFLogxK
U2 - 10.1007/s10822-012-9623-5
DO - 10.1007/s10822-012-9623-5
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AN - SCOPUS:84874109414
SN - 0920-654X
VL - 27
SP - 31
EP - 43
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 1
ER -
