Method to generate highly stable D-amino acid analogs of bioactive helical peptides using a mirror image of the entire PDB
| Autor: | Michael Garton, Tracy A. Stone, Philip M. Kim, Kyle Ethan Wang, Charles M. Deber, Satra Nim |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
D-amino acid Protein Conformation Peptidomimetic Protein Data Bank (RCSB PDB) Peptide Computational biology Protein Engineering 010402 general chemistry 01 natural sciences Glucagon-Like Peptide-1 Receptor 03 medical and health sciences Protein structure Glucagon-Like Peptide 1 Humans biologics D-analog Amino Acids Databases Protein Receptor Parathyroid Hormone Type 1 chemistry.chemical_classification Multidisciplinary Reproducibility of Results computer.file_format Protein engineering Biological Sciences Protein Data Bank Small molecule peptide 0104 chemical sciences 3. Good health Amino acid Biophysics and Computational Biology HEK293 Cells 030104 developmental biology chemistry Parathyroid Hormone peptidomimetics Peptides computer Algorithms Half-Life |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1711837115 |
| Popis: | Significance Using D-amino acids as the building blocks for bioactive peptides can dramatically increase their potency. However, simply swapping regular levorotary amino acids for dextrorotary (D)-amino acids alters the peptide surface topology and function is lost. Current methods to overcome this are not generally applicable and exclude the majority of therapeutic targets. By creating a mirror image of all 111,867 protein structures in the Protein Data Bank (PDB), we convert this repository into a D-peptide database with 2.8 million D-peptide structures. This D-PDB can be searched to find therapeutically active topologies, demonstrated here by the discovery of D-peptide GLP1R and PTH1R agonists. Evaluation of D-PDB coverage suggests that it holds candidates for most therapeutic targets and, thus, potentially contains hundreds of potent drug leads. Biologics are a rapidly growing class of therapeutics with many advantages over traditional small molecule drugs. A major obstacle to their development is that proteins and peptides are easily destroyed by proteases and, thus, typically have prohibitively short half-lives in human gut, plasma, and cells. One of the most effective ways to prevent degradation is to engineer analogs from dextrorotary (D)-amino acids, with up to 105-fold improvements in potency reported. We here propose a general peptide-engineering platform that overcomes limitations of previous methods. By creating a mirror image of every structure in the Protein Data Bank (PDB), we generate a database of ∼2.8 million D-peptides. To obtain a D-analog of a given peptide, we search the (D)-PDB for similar configurations of its critical—“hotspot”—residues. As a proof of concept, we apply our method to two peptides that are Food and Drug Administration approved as therapeutics for diabetes and osteoporosis, respectively. We obtain D-analogs that activate the GLP1 and PTH1 receptors with the same efficacy as their natural counterparts and show greatly increased half-life. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|