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.
16 amino acidsmaximum ring size achieved with maintained cell permeability
What the researchers 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.
Why it 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 numbers in context
Cyclic CPP with d-Pro-l-Pro motif achieved efficient cell entry and maintained binding affinity.
How the study worked
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.
Who was studied
Cell-based assays with engineered cyclic peptides
What this study cannot 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.
How to read the evidence
Proof-of-concept in vitro study demonstrating peptide design principles and biological activity. Pre-clinical stage.
When this study was published
Published in 2020. Cell-permeable peptide design continues to be an active and evolving research area.
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.
Questions still open
- 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?
Common questions
Why can't most peptides get inside cells?
What is the Grb2 SH2 domain?
Read the original research
Rational design of cell-permeable cyclic peptides containing a d-Pro-l-Pro motif.
Bioorganic & medicinal chemistry, 28(20), 115711
Citation
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