New Design Strategy Makes Cyclic Peptides Able to Enter Cells and Hit Intracellular Targets
A d-Pro-l-Pro motif enables rational design of cell-permeable cyclic peptides up to 16 amino acids, demonstrated with a potent Grb2 SH2 domain inhibitor.
Quick Facts
What This Study Found
The d-Pro-l-Pro motif permitted rational design of cell-permeable cyclic peptides up to 16 amino acids in ring size, including a biologically active inhibitor of the Grb2 SH2 domain.
Key Numbers
Cyclic CPP with d-Pro-l-Pro motif achieved efficient cell entry and maintained binding affinity.
How They Did This
Peptide synthesis and screening for cell-penetrating properties, followed by multidimensional NMR spectroscopy and circular dichroism analysis of peptide structures. Biological activity confirmed via Grb2 SH2 domain binding assays.
Why This Research Matters
Many important drug targets are inside cells and currently undruggable by peptides. This design strategy could unlock a new class of peptide therapeutics capable of reaching intracellular protein-protein interaction targets.
The Bigger Picture
The pharmaceutical industry has long sought to combine the target specificity of large biologics with the cell permeability of small molecules. Cell-permeable cyclic peptides represent a middle ground that could address 'undruggable' intracellular targets like protein-protein interactions.
What This Study Doesn't Tell Us
Demonstrated primarily in cell culture systems. In vivo pharmacokinetics, stability, and therapeutic efficacy remain to be established. The approach may not work equally well for all cargo types or target proteins.
Questions This Raises
- ?How do these cell-permeable cyclic peptides perform in animal models of disease?
- ?Can this design principle be applied to create peptide inhibitors for other intracellular protein-protein interactions?
- ?What is the metabolic stability of these cyclic peptides in vivo?
Trust & Context
- Key Stat:
- 16 amino acids maximum ring size achieved with maintained cell permeability
- Evidence Grade:
- Proof-of-concept in vitro study demonstrating peptide design principles and biological activity. Pre-clinical stage.
- Study Age:
- Published in 2020. Cell-permeable peptide design continues to be an active and evolving research area.
- Original Title:
- Rational design of cell-permeable cyclic peptides containing a d-Pro-l-Pro motif.
- Published In:
- Bioorganic & medicinal chemistry, 28(20), 115711 (2020)
- Authors:
- Wen, Jin, Liao, Hui, Stachowski, Kye, Hempfling, Jordan P, Qian, Ziqing, Yuan, Chunhua, Foster, Mark P, Pei, Dehua
- Database ID:
- RPEP-05196
Evidence Hierarchy
Frequently Asked Questions
Why can't most peptides get inside cells?
Peptides are generally too large and too polar to cross cell membranes passively, which limits their therapeutic use to targets on the cell surface or outside cells.
What is the Grb2 SH2 domain?
Grb2 is a signaling protein involved in growth factor pathways that drive cancer. Its SH2 domain mediates key protein interactions, making it a valuable drug target.
Read More on RethinkPeptides
Cite This Study
https://rethinkpeptides.com/research/RPEP-05196APA
Wen, Jin; Liao, Hui; Stachowski, Kye; Hempfling, Jordan P; Qian, Ziqing; Yuan, Chunhua; Foster, Mark P; Pei, Dehua. (2020). Rational design of cell-permeable cyclic peptides containing a d-Pro-l-Pro motif.. Bioorganic & medicinal chemistry, 28(20), 115711. https://doi.org/10.1016/j.bmc.2020.115711
MLA
Wen, Jin, et al. "Rational design of cell-permeable cyclic peptides containing a d-Pro-l-Pro motif.." Bioorganic & medicinal chemistry, 2020. https://doi.org/10.1016/j.bmc.2020.115711
RethinkPeptides
RethinkPeptides Research Database. "Rational design of cell-permeable cyclic peptides containing..." RPEP-05196. Retrieved from https://rethinkpeptides.com/research/wen-2020-rational-design-of-cellpermeable
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.