Evolution of Potent and Stable Placental-Growth-Factor-1-Targeting CovX-Bodies from Phage Display Peptide Discovery

详细信息    查看全文

• 作者：Kristen E. Bower ; Son N. Lam ; Bryan D. Oates ; Joselyn R. del Rosario ; Emily Corner ; Trina F. Osothprarop ; Arvind G. Kinhikar ; Julie A. Hoye ; R. Ryan Preston ; Robert E. Murphy ; Lioudmila A. Campbell ; Hanhua Huang ; Judith Jimenez ; Xia Cao ; Gang Chen ; Zemeda W. Ainekulu ; Aakash B. Datt ; Nancy J. Levin ; Venkata R. Doppalapudi ; Steven R. Pirie-Shepherd ; Curt Bradshaw ; Gary Woodnutt ; Rodney W. Lappe
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1256-1265
• 全文大小：1029K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

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 IC₅₀ values in PlGF-1/VEGFR-1 competition ELISA from 100 to 1 渭M. 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 IC₅₀ to 0.4 nM and increased compound stability from 5% remaining at 6 h after injection to 35% remaining at 24 h with a 尾 phase half-life of 75 h in mice. In cynomolgus monkey, a 78 h 尾 half-life was observed for lead compound 2. The pharmacological properties of 2 are currently being explored.