Journal
PROTEIN SCIENCE
Volume 18, Issue 10, Pages 2053-2059Publisher
WILEY
DOI: 10.1002/pro.217
Keywords
proligand; bacterial display; peptide libraries; vascular endothelial growth factor (VEGF); matrix metalloprotease 2 (MMP-2); protease regulation
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Funding
- Center of Cancer Nanotechnology Excellence (CCNE) [5 U54 CA119335-04]
- Program of Excellence in Nanotechnology [5 U01 HL080718-04]
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A general method was developed for the discovery of protease-activated binding ligands, or proligands, from combinatorial prodomain libraries displayed on the surface of E. coli. Peptide libraries of candidate prodomains were fused with a matrix metalloprotease-2 substrate linker to a vascular endothelial growth factor-binding peptide and sorted using a two-stage flow cytometry screening procedure to isolate proligands that required protease treatment for binding activity. Prodomains that imparted protease-mediated switching activity were identified after three sorting cycles using two unique library design strategies. The best performing proligand exhibited a 100-fold improvement in apparent binding affinity after exposure to protease. This method may prove useful for developing therapeutic and diagnostic ligands with improved systemic targeting specificity.
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