# US 9,901,617 B2 · Cell permeable inhibitors of the scaffold protein plenty of SH3 domains (POSH) or Sh3Rfl

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 9,901,617 B2
- Document ID: US9901617B2
- Status: Granted
- Kind: B2
- Application number: 14/911,939
- Filed: 2014-08-14
- Published: 2016-07-07
- Granted: 2018-02-27
- Earliest claimed: 2013-08-14
- Assignees: The Curators of the University of Missouri
- Applicants: The Curators of the University of Missouri
- Inventors: Mark A. Daniels
- Web page: https://patentgrep.com/patent/US9901617B2

## CPC

- A61K 38/1709: {from mammals}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/005: from viruses
- C07K 14/47: from mammals
- C12N 7/00: Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00)
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/00: Fusion polypeptide
- C07K 2319/10: containing a tag for extracellular membrane crossing, e.g. TAT or VP22
- C12N 2740/16322: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2740/16371: Demonstrated in vivo effect
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 5)

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

### Claim 7 (depends on 1)

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

### Claim 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.

### Claim 9 (depends on 8)

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).

### Claim 10 (depends on 8)

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.