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Biomaterials, Available online 28 March 2020, 120000 | https://doi.org/10.1016/j.biomaterials.2020.120000 Dual peptide-dendrimer conjugate inhibits acetylation of transforming growth factor β-induced protein and improves survival in sepsis

Wonhwa Lee^a,b,*, Eun Ji Park^c,d,*, Oh Kwang Kwon^a, Hyelim Kim^e, Youngbum Yoo^b, Shin-Woo Kim^f, Young-Kyo Seo^b, In-San Kim^g,h, Dong Hee Na^c,*, Jong-Sup Bae^a,*

^aCollege of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, BK21 Plus KNU Multi-Omics Based Creative Drug Research Team, Kyungpook National University, Daegu, 41566, Republic of Korea
^bAging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea
^cCollege of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea
^dD&D Pharmatech, Seongnam, Gyeonggi-do, 13486, Republic of Korea
^eCollege of Pharmacy, Chungnam National University, Daejeon, 34134, Republic of Korea
^fDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea
^gBiomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
^hKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea

^*Corresponding author

Abstract

Sepsis is a potentially fatal complication of infections and there are currently no effective therapeutic options for severe sepsis. In this study, we revealed the secretion mechanism of transforming growth factor β-induced protein (TGFBIp) that was recently identified as a therapeutic target for sepsis, and designed TGFBIp acetylation inhibitory peptide (TAIP) that suppresses acetylation of lysine 676 in TGFBIp. To improve bioavailability and biodegradation of the peptide, TAIP was conjugated to polyamidoamine (PAMAM) dendrimers. Additionally, the cell-penetrating peptide (CPP) was conjugated to the TAIP-modified PAMAM dendrimers for the intracellular delivery of TGFBIp. The resulting nanostructures, decorated with TAIP and CPP via poly (ethylene glycol) linkage, improved the mortality and organ damage in the septic mouse model and suppressed lipopolysaccharide-activated severe vascular inflammatory responses in endothelial cells. Thus, the dendrimer-based nanostructures for delivery of TAIP using CPP show great promise in practical applications in sepsis therapy.

논문정보

형식Research article
게재일2020년 03월 (BRIC 등록일 2020-04-02)
연구진국내 연구진
분야 의약학 > 약학

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