CendR
CendR (C-end Rule) is a position-dependent protein motif that regulates cellular uptake and vascular permeability through interaction with neuropilin-1.[1] The CendR motif has a consensus (R/K)XX(R/K) and it is able to interact with its receptor only when the second basic residue is exposed at the C-terminus.
Mechanism of action[edit]
C-terminal CendR motif engages with widely expressed neuropilin-1 receptors to trigger an increased permeability of the vasculature and penetration of tissue parenchyma by an endocytotic/exocytotic transport mechanism.[2] The CendR pathway starts with an endocytosis step that is distinct from known endocytosis pathways. It most closely resembles macropinocytosis, but unlike macropinocytosis, the CendR pathway is receptor (neuropilin)-initiated and its activity is controlled by the nutrient status of the cell or tissue.[3] CendR is an active transport process that requires energy.[4] It is not limited to extravasation, but also includes penetration of tissue parenchyma, potentially via cell-to-cell transport. CendR elements that are not C-terminally exposed are unable to bind to neuropilin-1. However, such cryptic CendR elements can be activated by proteolytic cleavage (e.g. by furin, urokinase type plasminogen activator, and other proteases of suitable substrate specificity).
Clinical significance[edit]
The CendR pathway is used to enhance transport of coupled and co-administered anti-cancer drugs into tumors. Tumor penetrating peptides (TPP, a class of tumor homing peptides containing a cryptic CendR motif) activate tumor specific transport through a three-step process that involves binding to a primary tumor-specific receptor, a proteolytic activation of CendR element, and binding to NRP-1 to activate the trans-tissue transport pathway.[5] Clinical-stage prototypic CendR peptide iRGD, developed by Lisata Therapeutics as LSTA1, is utilized to make solid tumors temporarily more accessible to circulating anti-cancer drugs to increase their therapeutic index. Several viruses, including the SARS-CoV2 coronavirus, are also using the CendR system for cellular entry and tissue penetration, and it is known that viruses that have the system are more virulent and deadly.[6]
References[edit]
- ^ Ruoslahti E (February 2017). "Tumor penetrating peptides for improved drug delivery". Advanced Drug Delivery Reviews. 110–111 (Supplement C): 3–12. doi:10.1016/j.addr.2016.03.008. PMC 5045823. PMID 27040947.
- ^ Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E (September 2009). "C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration". Proceedings of the National Academy of Sciences of the United States of America. 106 (38): 16157–62. Bibcode:2009PNAS..10616157T. doi:10.1073/pnas.0908201106. PMC 2752543. PMID 19805273.
- ^ Pang H, Braun GB, Friman T, Aza-Blanc P, Ruidiaz ME, Sugahara KN, Teesalu T, Ruoslahti E (October 2014). "An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability". Nature Communications. 3 (5): 4904. Bibcode:2014NatCo...5.4904P. doi:10.1038/ncomms5904. PMC 4185402. PMID 25277522.
- ^ Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy A, Girard OM, Hanahan D, Mattrey R, Ruoslahti E (Dec 2009). "Tissue-penetrating delivery of compounds and nanoparticles into tumors". Cancer Cell. 16 (6): 510–20. doi:10.1016/j.ccr.2009.10.013. PMC 2791543. PMID 19962669.
- ^ Teesalu T, Sugahara KN, Ruoslahti E (August 2014). "Tumor penetrating peptides". Frontiers in Oncology. 3 (3): 216. doi:10.3389/fonc.2013.00216. PMC 3753659. PMID 23986882.
- ^ Balistreri G, Yamauchi Y, Teesalu T (November 2021). "A widespread viral entry mechanism: The C-end Rule motif–neuropilin receptor interaction". Proceedings of the National Academy of Sciences of the United States of America. 118 (49): e2112457118. Bibcode:2021PNAS..11812457B. doi:10.1073/pnas.2112457118. hdl:10138/338091. PMC 8670474. PMID 34772761.