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

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

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

  1. ↑ 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.
  2. ↑ 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. doi:10.1073/pnas.0908201106. PMC 2752543. PMID 19805273.
  3. ↑ 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. doi:10.1038/ncomms5904. PMC 4185402. PMID 25277522.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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. doi:10.1073/pnas.2112457118. hdl:10138/338091. PMC 8670474. PMID 34772761.
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