dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis

Sangho Lim, Won Ju Kim, Yeon Ho Kim, Sohee Lee, Ja Hyun Koo, Jung Ah Lee, Heeseok Yoon, Do Hyun Kim, Hong Jai Park, Hye Mi Kim, Hong Gyun Lee, Ji Yun Kim, Jae Ung Lee, Jae Hun Shin, Lark Kyun Kim, Junsang Doh, Hongtae Kim, Sang Kyou Lee, Alfred L.M. Bothwell, Minah SuhJe Min Choi

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood-brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood-brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS.

Original languageEnglish
Article number8244
JournalNature communications
Volume6
DOIs
Publication statusPublished - 2015 Sep 15

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blood-brain barrier
central nervous system
T-cells
Autoimmune Experimental Encephalomyelitis
Neurology
Blood-Brain Barrier
CTLA-4 Antigen
Multiple Sclerosis
peptides
delivery
proteins
T-Lymphocytes
Peptides
lymphocytes
antigens
Central Nervous System
Central Nervous System Agents
Tissue
mice
Th17 Cells

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Lim, Sangho ; Kim, Won Ju ; Kim, Yeon Ho ; Lee, Sohee ; Koo, Ja Hyun ; Lee, Jung Ah ; Yoon, Heeseok ; Kim, Do Hyun ; Park, Hong Jai ; Kim, Hye Mi ; Lee, Hong Gyun ; Yun Kim, Ji ; Lee, Jae Ung ; Hun Shin, Jae ; Kyun Kim, Lark ; Doh, Junsang ; Kim, Hongtae ; Lee, Sang Kyou ; Bothwell, Alfred L.M. ; Suh, Minah ; Choi, Je Min. / dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis. In: Nature communications. 2015 ; Vol. 6.
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title = "dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis",
abstract = "Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood-brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood-brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS.",
author = "Sangho Lim and Kim, {Won Ju} and Kim, {Yeon Ho} and Sohee Lee and Koo, {Ja Hyun} and Lee, {Jung Ah} and Heeseok Yoon and Kim, {Do Hyun} and Park, {Hong Jai} and Kim, {Hye Mi} and Lee, {Hong Gyun} and {Yun Kim}, Ji and Lee, {Jae Ung} and {Hun Shin}, Jae and {Kyun Kim}, Lark and Junsang Doh and Hongtae Kim and Lee, {Sang Kyou} and Bothwell, {Alfred L.M.} and Minah Suh and Choi, {Je Min}",
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Lim, S, Kim, WJ, Kim, YH, Lee, S, Koo, JH, Lee, JA, Yoon, H, Kim, DH, Park, HJ, Kim, HM, Lee, HG, Yun Kim, J, Lee, JU, Hun Shin, J, Kyun Kim, L, Doh, J, Kim, H, Lee, SK, Bothwell, ALM, Suh, M & Choi, JM 2015, 'dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis', Nature communications, vol. 6, 8244. https://doi.org/10.1038/ncomms9244

dNP2 is a blood-brain barrier-permeable peptide enabling ctCTLA-4 protein delivery to ameliorate experimental autoimmune encephalomyelitis. / Lim, Sangho; Kim, Won Ju; Kim, Yeon Ho; Lee, Sohee; Koo, Ja Hyun; Lee, Jung Ah; Yoon, Heeseok; Kim, Do Hyun; Park, Hong Jai; Kim, Hye Mi; Lee, Hong Gyun; Yun Kim, Ji; Lee, Jae Ung; Hun Shin, Jae; Kyun Kim, Lark; Doh, Junsang; Kim, Hongtae; Lee, Sang Kyou; Bothwell, Alfred L.M.; Suh, Minah; Choi, Je Min.

In: Nature communications, Vol. 6, 8244, 15.09.2015.

Research output: Contribution to journalArticle

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AU - Kim, Won Ju

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AU - Lee, Sohee

AU - Koo, Ja Hyun

AU - Lee, Jung Ah

AU - Yoon, Heeseok

AU - Kim, Do Hyun

AU - Park, Hong Jai

AU - Kim, Hye Mi

AU - Lee, Hong Gyun

AU - Yun Kim, Ji

AU - Lee, Jae Ung

AU - Hun Shin, Jae

AU - Kyun Kim, Lark

AU - Doh, Junsang

AU - Kim, Hongtae

AU - Lee, Sang Kyou

AU - Bothwell, Alfred L.M.

AU - Suh, Minah

AU - Choi, Je Min

PY - 2015/9/15

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N2 - Central nervous system (CNS)-infiltrating effector T cells play critical roles in the development and progression of multiple sclerosis (MS). However, current drugs for MS are very limited due to the difficulty of delivering drugs into the CNS. Here we identify a cell-permeable peptide, dNP2, which efficiently delivers proteins into mouse and human T cells, as well as various tissues. Moreover, it enters the brain tissue and resident cells through blood vessels by penetrating the tightly organized blood-brain barrier. The dNP2-conjugated cytoplasmic domain of cytotoxic T-lymphocyte antigen 4 (dNP2-ctCTLA-4) negatively regulates activated T cells and shows inhibitory effects on experimental autoimmune encephalomyelitis in both preventive and therapeutic mouse models, resulting in the reduction of demyelination and CNS-infiltrating T helper 1 and T helper 17 cells. Thus, this study demonstrates that dNP2 is a blood-brain barrier-permeable peptide and dNP2-ctCTLA-4 could be an effective agent for treating CNS inflammatory diseases such as MS.

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