Page 16 - M. Immunology

[M. Immunology-11]

Nuclear import inhibition of SRTFs with nuclear importin

binding peptide suppresses expression of pro-inflammatory

cytokines

Dongho Kim¹, Sanghyeon Yu¹, Misuk Baek¹, Mingu Kang¹, Hyemin Yu¹, Seokwon Lee¹, Sujeong Kim¹,

Youngsil Choi¹, Daewoong Jo¹˙*

¹R&D Institute, Cellivery Therapeutics, Inc., Seoul 03929, South Korea

Various stress responsive transcription factors (SRTFs), NF-κB, NFAT, STAT1 and AP-1 are activated to trigger innate

immunity against infection or trauma. To regulate the expression of inflammatory cytokines, improved cell-
permeable nuclear import inhibitor (iCP-NI) peptide has been developed by fusing sequence-optimized hydrophobic

cell-penetrating peptide (CPP) with nuclear localization signal (NLS) and demonstrated its improved therapeutic
applicability. iCP-NI prevented apoptosis by reducing cytokines (TNF-α: -48%, IL-6: -63% and IL-10: 1338%) and

elevated survivability (100%) in lipopolysaccharide (LPS)/D-galactosamine (D-gal)-induced hepatitis animals,
repeatedly (100/100 death in diluent, 133/133 survival in treatment group). To prove the clinical applicability of iCP-

NI in polymicrobial infection environment, mouse peritonitis models were developed by cecal slurry (CS) injection
or cecal ligation and puncture (CLP) surgery. The survivability of both models had been increased in the presence

of iCP-NI and meropenem (40%, 66% respectively) more than iCP-NI absence group. These results suggest that
iCP-NI has potential as a novel medicine to cure the various inflammatory disease such as sepsis which accompany

severe inflammatory disorder and cytokine storm.