Evolution of potent and stable placental-growth-factor-1-targeting CovX-bodies from phage display peptide discovery
| Autor: | Kristen E Bower, Ryan Preston, Emily Corner, Robert E. Murphy, Arvind G. Kinhikar, Xia Cao, Zemeda W Ainekulu, Aakash B Datt, Steven Pirie-Shepherd, Lioudmila Campbell, Gang Chen, Venkata Doppalapudi, Joselyn Del Rosario, Hanhua Huang, Bryan Oates, Rodney W. Lappe, Son Lam, Trina Osothprarop, Nancy Levin, Curt Bradshaw, Gary Woodnutt, Julie A Hoye, Judith Jimenez |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
Male
Models Molecular Phage display Molecular Sequence Data Peptide Enzyme-Linked Immunosorbent Assay Cross Reactions Pregnancy Proteins Binding Competitive Antibodies chemistry.chemical_compound Mice Structure-Activity Relationship Drug Stability In vivo Peptide Library Drug Discovery Structure–activity relationship Animals Humans Amino Acid Sequence Peptide library Peptide sequence Placenta Growth Factor chemistry.chemical_classification Vascular Endothelial Growth Factor Receptor-1 Molecular biology In vitro Macaca fascicularis chemistry Amino Acid Substitution Molecular Medicine Peptides Lead compound Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 54(5) |
| ISSN: | 1520-4804 |
| Popis: | Novel phage-derived peptides are the first reported molecules specifically targeting human placental growth factor 1 (PlGF-1). Phage data enabled peptide modifications that decreased IC(50) values in PlGF-1/VEGFR-1 competition ELISA from 100 to 1 μM. Peptides exhibiting enhanced potency were bioconjugated to the CovX antibody scaffold 1 (CVX-2000), generating bivalent CovX-Bodies with 2 nM K(D) against PlGF-1. In vitro and in vivo peptide cleavage mapping studies enabled the identification of proteolytic hotspots that were subsequently chemically modified. These changes decreased IC(50) to 0.4 nM and increased compound stability from 5% remaining at 6 h after injection to 35% remaining at 24 h with a β phase half-life of 75 h in mice. In cynomolgus monkey, a 78 h β half-life was observed for lead compound 2. The pharmacological properties of 2 are currently being explored. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|