期刊
CHEMBIOCHEM
卷 15, 期 3, 页码 451-459出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201300568
关键词
cyclic cystine ladder; drug design; integrin-binding; peptides; theta-defensins
资金
- Australian Research Council [DP0984390]
- NHMRC [APP1026501]
- University of Queensland International Scholarship
- NHMRC CDA [APP631420]
Peptides have the specificity and size required to target the protein-protein interactions involved in many diseases. Some cyclic peptides have been utilised as scaffolds for peptide drugs because of their stability; however, other cyclic peptide scaffolds remain to be explored. theta-Defensins are cyclic peptides from mammals; they are characterised by a cyclic cystine ladder motif and have low haemolytic and cytotoxic activity. Here we demonstrate the potential of the cyclic cystine ladder as a scaffold for peptide drug design by introducing the integrin-binding Arg-Gly-Asp (RGD) motif into the theta-defensin RTD-1. The most active analogue had an IC50 of 18 nm for the alpha(v)beta(3) integrin as well as high serum stability, thus demonstrating that a desired bioactivity can be imparted to the cyclic cystine ladder. This study highlights how theta-defensins can provide a stable and conformationally restrained scaffold for bioactive epitopes in a beta-strand or turn conformation. Furthermore, the symmetry of the cyclic cystine ladder presents the opportunity to design peptides with dual bioactive epitopes to increase activity and specificity.
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