Page 272 - ebook

[E. Immunology] E-5

Systemically-Delivered Nuclear Localization Signal Has

Therapeutic Potential To Treat Sepsis By Suppressing

Cytokine-Storm

Gyunam Kim¹, Dongho Kim¹, Sanghyeon Yu¹, Misuk Baek¹, Jaewook Lee¹, Hyunji Lee¹, Joohyun Pi¹,

Eunna Chung¹, Daewoong Jo¹*

¹New Drug Development Division, Cellviery Therapeutics, Inc., Seoul 121-904, Korea

Infection or trauma triggers inflammation by activating various inflammation-associated transcription factors (IATFs),

including NF-κB, AP-1, NFAT, and STAT1. The nuclear localization signal (NLS) of IATFs are recognized by the nuclear
transport protein, importin α, and the complex is translocated to the nucleus for expression of cytokines. However,

dysregulated expression of cytokines damages cells and organs, which is called as cytokine-storm. To regulate the
uncontrolled cytokines, improved Cell-Permeable nuclear import inhibitor (iCP-NI) has been developed by fusing

hydrophobic cell-penetrating peptide with NLS, and demonstrated its improved therapeutic applicability. To prove
the efficacy of iCP-NI in sepsis, peritonitis models were developed by cecal slurry (CS) injection and cecal ligation

and puncture (CLP) surgery. These peritonitis mice were administered with iCP-NI (30 mg/kg, QD) & meropenem
(the standard care antibiotics) via intravenously. As a result, the mice administered with iCP-NI & meropenem

showed increased survivability than mice that only received meropenem (CLP-induced peritonitis: +44%, CS-induced
peritonitis: +76%), and cytokines decreased 3 hours after administration (TNF-α: -81%, IL-6: -68% & MCP-1: -51%)

in CLP-induced peritonitis mice. These results suggest that iCP-NI has potential as a novel medicine to cure various
acute inflammatory diseases such as sepsis, which accompany severe inflammatory disorder and cytokine-storm.