Cell permeable inhibitors of the scaffold protein plenty of SH3 domains (POSH) or Sh3Rfl

Patent metadata

Field	Value
Publication number	US-9901617-B2
Application number	US-201414911939-A
Country	US
Kind code	B2
Filing date	Aug 14, 2014
Priority date	Aug 14, 2013
Publication date	Feb 27, 2018
Grant date	Feb 27, 2018

Abstract

Here, we identify Plenty of SH3 (POSH) and JNK-interacting protein 1 (JIP-1) as a multi-protein scaffold network for TCR-mediated JNK1 activation in CD8 + T-cells. Disruption of the POSH/JIP-1 complex led to profound defects in the activation of JNK1, as well as deficient activation or induction of the transcription factors c-Jun, T-bet and Eomesodermin. Furthermore, disruption of the POSH/JIP complex in CD8 + T-cells resulted in impaired proliferation, decreased cytokine expression and the inability to control tumors. Collectively, these data identify a mechanism for the specific regulation of TCR-dependent JNK1 activation and function that is key for CD8 + T-cell responses. A group of compounds are described that individually or in concert target a common set of biological pathways important in T cell function, activation of innate inflammation, ischemic reperfusion injury, HIV release and oncogenesis.

First claim

What is claimed is:

1. A composition comprising at least one chimeric peptide, wherein the at least one chimeric peptide comprises: i) a first amino acid portion comprising the amino acid sequence selected from the group consisting of: EGKEPGDLKFSKGDIIILRR (SEQ ID NO: 1); KEADKDCLPFAKDDVLTVIR (SEQ ID NO: 2); RKEDELELRKGEMFLVFER (SEQ ID NO: 3); PQSEAELELKEGDIVFVHKK (SEQ ID NO: 4); and an amino acid sequence having over its total length at least 85% sequence identity with any one of SEQ ID NOs: 1 to 4; and ii) a second amino acid portion comprising a cell internalization moiety adapted to internalize the at least one chimeric peptide into a cell to bind to POSH (Plenty of SH3 Domains) for inhibiting and disrupting POSH scaffold networks.

2. The composition of claim 1 , wherein the first amino acid portion comprises an amino acid sequence having over at least 90% overall sequence identity with any one of SEQ ID NOs: 1 to 4.

3. The composition of claim 1 , wherein the first amino acid portion is of mammalian origin.

4. The composition of claim 1 , wherein the first amino acid portion is encoded by a nucleic acid sequence.

5. The composition of claim 1 in which the cell internalization moiety comprises a peptide of HIV tat.

6. The composition of claim 5 , in which the cell internalization moiety comprises the amino acid sequence of GRKKRRQRRR (SEQ ID NO: 5).

7. The composition of claim 1 , wherein the composition is a pharmaceutical composition together with one or more pharmaceutically acceptable carrier and/or excipients.

8. A chimeric peptide comprising a peptide sequence for inhibiting and disrupting POSH scaffold networks and a protein transduction domain, wherein the peptide sequence comprises the amino acid sequence selected from the group consisting of: EGKEYGDLKESKGDIIILRR (SEQ ID NO: 1); KEADKDCLPFAKDDVLTVIR (SEQ ID NO: 2); RKEDELELRKGEMFLVFER (SEQ ID NO: 3); PQSEAELELKEGDIVFVHKK (SEQ ID NO: 4); and an amino acid sequence having over its total length at least 85% sequence identity with any one of SEQ ID NOs: 1 to 4.

9. The chimeric peptide of claim 8 , wherein the protein transduction domain comprises a peptide of HIV tat comprising the amino acid sequence of GRKKRRQRRR (SEQ ID NO: 5).

10. A pharmaceutical composition comprising at least one peptide of claim 8 as active ingredient, together with one or more pharmaceutically acceptable carrier and/or excipients.

Assignees

• Univ Missouri

Inventors

• Daniels Mark A

Classifications

• C12N2740/16371

  Demonstrated in vivo effect · CPC title

• C12N2740/16322

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title

• C12N7/00

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• A61K38/1709 Primary

  from mammals · CPC title

• C07K2319/10

  containing a tag for extracellular membrane crossing, e.g. TAT or VP22 · CPC title