C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration
Open accessAbstract
Screening of phage libraries expressing random peptides for binding to prostate cancer cells primarily yielded peptides that had a C-terminal arginine (or rarely lysine) residue, usually in a consensus context R/KXXR/K. Phage expressing these sequences and synthetic nanoparticles coated with them bound to and were internalized into cells. The C-terminal arginine (or lysine) was essential to the activity; adding another amino acid, or even blocking the free carboxyl group of this arginine residue by amidation, eliminated the binding and internalizing activity. An internal R/KXXR/K can be exposed and switched on by a cleavage by a protease. The strict requirement for C-terminal exposure of the motif prompted us to term the phenomenon the C-end rule (CendR). Affinity chromatography showed that the CendR peptides bind to neuropilin-1 (NRP-1) on the target cells. NRP-1 is a cell-surface receptor that plays an essential role in angiogenesis, regulation of vascular permeability, and the development of the nervous system. VEGF-A165 and other ligands of NRP-1 possess a C-terminal CendR sequence that interacts with the b1 domain of NRP-1 and causes cellular internalization and vascular leakage. Our CendR peptides have similar effects, particularly when made multivalent through coupling to a particle. We also noted a unique and important activity of these peptides: penetration and transportation through tissues. The peptides were able to take payloads up to the nanoparticle size scale deep into extravascular tissue. Our observations have implications in drug delivery and penetration of tissue barriers and tumors.
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The C-terminal motif of the cleaved S1 subunit can bind to neuropillin-1 (NRP-1), which negatively influences T cell memory.
“Interestingly, the C-terminal motif of the cleaved S1 subunit can bind to neuropillin-1 (NRP-1),67,68 which negatively influences T cell memory.69”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [67]
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- Authors
- Teesalu, T., Sugahara, K. N., Kotamraju, V. R., & Ruoslahti, E.
- Affiliations
- University of California, Santa Barbara (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-09-22
- Volume
- 106
- Issue
- 38
- Pages
- 16157-16162
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2752543
- OpenAlex
- W1989658253
- Cited by
- 812
- References
- 37
- Citations by year
- 2026: 33 · 2025: 50 · 2024: 35 · 2023: 60 · 2022: 80 · 2021: 87 · 2020: 75 · 2019: 53 · 2018: 57 · 2017: 56 · 2016: 35 · 2015: 47 · 2014: 42 · 2013: 39 · 2012: 25
- FWCI
- 8.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Defense (W81XWH)
- National Institutes of Health (7p01ca104898-05)
- National Cancer Institute (R01CA115410, P01-CA104898, R01CA119414, U54CA119335, CA104898, CA 119335, CA119414, CA115410)
- Topics
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- neuropilin-1, C-terminal arginine, phage display, peptide internalization, nanoparticle targeting, tissue penetration, vascular leakage, VEGF165, B1 domain, tumor drug delivery, prostate cancer cells, angiogenesis
- MeSH terms
- Amino Acid Sequence, Animals, Arginine, Binding Sites, Binding, Competitive, Chromatography, Affinity, Endocytosis, Humans, Lung, Male, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Peptide Fragments, Peptides, Prostatic Neoplasms, Protein Binding, Tissue Distribution, Transfection, Transplantation, Heterologous, Microscopy, Confocal, Peptide Library, Neuropilin-1, Vascular Endothelial Growth Factor A, Cell Line, Tumor, Mice
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