Designed peptides for tight junction barrier modulation

Patent metadata

Field	Value
Publication number	US-2016199440-A1
Application number	US-201414912098-A
Country	US
Kind code	A1
Filing date	Aug 18, 2014
Priority date	Aug 16, 2013
Publication date	Jul 14, 2016
Grant date	—

Abstract

According to aspects illustrated herein, there is provided an agent that transiently disrupts claudin-1 within tight junctions. The agent includes a peptide having at least 40% polar, uncharged amino acid residues and a self-assembled β-sheet secondary structure. According to aspects illustrated herein, there is also provided a transepithelial drug and vaccine formulations, as well as isolated peptides, pharmaceutical compositions, and transdermal delivery devices. Also described herein are methods of disrupting epithelial barrier and methods of administering the transepithelial formulations described herein.

First claim

1 . A transepithelial drug formulation comprising:
a pharmaceutically suitable carrier; an effective amount of a therapeutic agent; and an agent that transiently disrupts claudin-1 within tight junctions, wherein the agent comprises a peptide including at least 40% polar, uncharged amino acid residues and a self-assembled β-sheet secondary structure.

2 . The transepithelial drug formulation according to claim 1 , wherein the peptide does not consist of the amino acid sequence of
SSVSQSTGQIQSKVFDSLLNLNSTLQATR (SEQ ID NO:1), SCVSQSTGQIQCKVFDSLLNLNSTLQAT (SEQ ID NO:2), SSVSQSTGQIQSKVFDSLLNLSSTLQAT (SEQ ID NO:3), or SCVSQSTGQ[I/V]QCKVFDSLLNLSSTLQAT (SEQ ID NO:4).

3 . The transepithelial drug formulation according to claim 1 , wherein the drug formulation is a transdermal or transmucosal drug formulation.

4 . The transepithelial drug formulation according to claim 1 , wherein the transepithelial drug formulation comprises a plurality of the peptides and wherein the plurality of the peptides forms one or more fibrils.

5 . The transepithelial drug formulation according to claim 1 , wherein the amino acid sequence of the peptide comprises at least 50% polar, uncharged amino acid residues.

6 . The transepithelial drug formulation according to claim 5 , wherein the amino acid sequence of the peptide comprises at least 60% polar, uncharged amino acid residues.

7 . The transepithelial drug formulation according to claim 1 , wherein the peptide comprises an amino acid sequence of at least 6 amino acid residues.

8 . The transepithelial drug formulation according to claim 1 , wherein the peptide comprises an amino acid sequence of less than 53 amino acid residues.

9 . The transepithelial drug formulation according to claim 1 , wherein the peptide comprises an amino acid sequence of 6 to 30 amino acid residues.

10 . The transepithelial drug formulation according to claim 9 , wherein the peptide comprises the amino acid sequence of SSVSQSTGQIQSKVFDSLLNLSSTLQATR (SEQ ID NO: 5), SILTGVSTLDQSLKQLSNFSQAVSTQSSR (SEQ ID NO:6), GGMSCVSQSTGQIQCKV (SEQ ID NO:7), SCVSQSTGQIQCKV (SEQ ID NO:8), RRGSCVSQSGRR (SEQ ID NO: 9), ISGVQCCQTKQSS (SEQ ID NO: 10), RRGVCSSSQGRR (SEQ ID NO:11), LWMSSVSQSTGQIQSKVFDS (SEQ ID NO:12), MSSVSQSTGQIQSKVFDS (SEQ ID NO:13), MSSVSQSTGQIQSKV (SEQ ID NO:14), MSSVSQST (SEQ ID NO:15), ISMSQQVSQSGVSDKFST (SEQ ID NO:16), SIMSGKQSSVQSQVT (SEQ ID NO:17), VSMSSTSQ (SEQ ID NO:18), VSSSSQ (SEQ ID NO:19), SILTGVST (SEQ ID NO:20), SSVSQSTG (SEQ ID NO:21), GQIQSKVG (SEQ ID NO:22), LNLSSTLQG (SEQ ID NO:23), NSVVQSTG (SEQ ID NO:24), GQMQSKVG (SEQ ID NO:25), or SCVSQSTGQIQCKVFDSLLNLSSTLQATR (SEQ ID NO:26).

11 . The transepithelial drug formulation according to claim 1 , wherein the peptide is a scrambled form of a claudin-1 amino acid sequence, wherein the claudin-1 amino acid sequence comprises at least 6 amino acid residues of an extracellular loop region of claudin-1.

12 . The transepithelial drug formulation according to claim 11 , wherein the claudin-1 amino acid sequence comprises one or more cysteine to serine substitutions.

13 . The transepithelial drug formulation according to claim 11 , wherein the peptide comprises the amino acid sequence of SILTGVSTLDQSLKQLSNFSQAVSTQSSR (SEQ ID NO:6), ISGVQCCQTKQSS (SEQ ID NO:10), RRGVCSSSQGRR (SEQ ID NO:11), ISMSQQVSQSGVSDKFST (SEQ ID NO:16), SIMSGKQSSVQSQVT (SEQ ID NO:17), VSMSSTSQ (SEQ ID NO:18), VSSSSQ (SEQ ID NO:19), or SILTGVST (SEQ ID NO:20).

14 . The transepithelial drug formulation according to claim 1 , wherein the agent consists of the peptide.

15 . The transepithelial drug formulation according to claim 1 , wherein the carrier includes a surfactant.

16 .- 22 . (canceled)

23 . A transepithelial vaccine formulation comprising:
a pharmaceutically suitable carrier; an effective amount of an antigen or antigen-encoding nucleic acid molecule present in the carrier, and optionally one or more adjuvants; and an agent that transiently disrupts claudin-1 within tight junctions, wherein the agent comprises a peptide including at least 40% polar, uncharged amino acid residues and a self-assembled β-sheet secondary structure.

24 .- 53 . (canceled)

54 . A pharmaceutical composition comprising:
an isolated peptide comprising the amino acid sequence selected from the group consisting of SSVSQSTGQIQSKVFDSLLNLSSTLQATR (SEQ ID NO: 5), SILTGVSTLDQSLKQLSNFSQAVSTQSSR (SEQ ID NO:6), GGMSCVSQSTGQIQCKV (SEQ ID NO:7), SCVSQSTGQIQCKV (SEQ ID NO:8), RRGSCVSQSGRR (SEQ ID NO: 9), ISGVQCCQTKQSS (SEQ ID NO: 10), RRGVCSSSQGRR (SEQ ID NO:11), LWMSSVSQSTGQIQSKVFDS (SEQ ID NO:12), MSSVSQSTGQIQSKVFDS (SEQ ID NO:13), MSSVSQSTGQIQSKV (SEQ ID NO:14), MSSVSQST (SEQ ID NO:15), ISMSQQVSQSGVSDKFST (SEQ ID NO:16), SIMSGKQSSVQSQVT (SEQ ID NO:17), VSMSSTSQ (SEQ ID NO:18), VSSSSQ (SEQ ID NO:19), SILTGVST (SEQ ID NO:20), SSVSQSTG (SEQ ID NO:21), GQIQSKVG (SEQ ID NO:22), LNLSSTLQG (SEQ ID NO:23), NSVVQSTG (SEQ ID NO:24), GQMQSKVG (SEQ ID NO:25), and SCVSQSTGQIQCKVFDSLLNLSSTLQATR (SEQ ID NO:26); and a pharmaceutically suitable carrier.

55 .- 56 . (canceled)

57 . The pharmaceutical composition according to claim 55 further comprising:
a therapeutic agent.

58 . (canceled)

59 . A method of disrupting an epithelial barrier comprising:
applying to an epithelial site an amount of an agent that transiently disrupts claudin-1 within tight junctions that is effective to disrupt claudin-1 in epithelial cells present at the site, wherein the agent comprises a peptide including at least 40% polar, uncharged amino acid residues and a self-assembled β-sheet secondary structure, thereby disrupting barrier formation at the epithelial site.

60 .- 64 . (canceled)

Assignees

• Miller Benjamin L
• De Benedetto Anna
• Beck Lisa A
• Anderson Elizabeth A
• Univ Rochester

Inventors

• Miller Benjamin L
• De Benedetto Anna
• Beck Lisa A
• Anderson Elizabeth A

Classifications

• A61K9/0043

  Nose · CPC title

• A61K2039/543

  intranasal · CPC title

• A61K39/39

  characterised by the immunostimulating additives, e.g. chemical adjuvants · CPC title

• A61K38/44

  Oxidoreductases (1) · CPC title

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title