Abstract
The lack of progress in developing targeted therapeutics directed at protein–protein complexes has been due to the absence of well-defined ligand-binding pockets and the extensive intermolecular contacts at the protein–protein interface. Our laboratory has developed approaches to dissect protein–protein complexes focusing on the superfamilies of erbB and tumor necrosis factor (TNF) receptors by the combined use of structural biology and computational biology to facilitate small molecule development. We present a perspective on the development and application of peptide inhibitors as well as immunoadhesins to cell surface receptors performed in our laboratory.
Highlights
Therapeutic development, small molecule drug creation, has focused on enzymes
We concentrated on efforts to create small exocyclic constrained peptide mimicking flexible loops [26,27,34,35], and we realized that a protein–protein interaction mediated by flexible loops tends to more dynamic
Her2-associated dimeric meric receptors, we focused on generating other peptides based on the structural features receptors, we focused on generating other peptides based on the structural features of S22
Summary
Therapeutic development, small molecule drug creation, has focused on enzymes. A variety of methods have been developed to target certain molecular complexes and include high throughput screening, phage display against protein complexes, and alteration of biological activities using antibodies and recombinant proteins [11,12,13]. Peptide inhibitors are ideally suited to overcome these limitations and to create novel molecules beyond monoclonal antibodies. Due to their small size, peptides are amenable for chemical modifications to attain clinically relevant pharmacological features, and their structural features may facilitate small non-peptidic inhibitor development. In addition to using peptides as therapeutics per se, novel approaches using peptide inhibitors are being adopted These approaches include cell-permeable peptides [18], peptide-based cancer vaccines, and peptide-decorated nanoparticles for diagnostics and drug-delivery. Based on the fundamental structural features of protein–protein complexes, we have developed a method to design and develop constrained peptide mimics specific for interaction surfaces using computational and structural biology approaches
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