TARGETING PEPTIDES THAT BIND S. MUTANS, CONSTRUCTS COMPRISING SUCH PEPTIDES AND USES THEREOF

• US 20160031941A1
• Filed: 07/08/2015
• Published: 02/04/2016
• Est. Priority Date: 07/11/2014
• Status: Abandoned Application

• Current Assignee: C3 Jian, Inc.
• Original Assignee: C3 Jian, Inc.
• Inventors: Eckert, Randal H., Varnum, Brian C., Kaplan, Christopher W., Kyme, Pierre A.
• Application Number:
  US14/794,609
• Publication Number:
  US 20160031941A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2800/81 Preparation or application process involves irradiation
• CPC Class Codes: A61K 38/10 Peptides having 12 to 20 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 41/0057 Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
• CPC Class Codes: 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
• CPC Class Codes: A61K 8/64 Proteins; Peptides; Derivatives or degradation products thereof
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: A61Q 17/005 Antimicrobial preparations
• CPC Class Codes: C07K 14/315 from Streptococcus (G), e.g. Enterococci
• CPC Class Codes: C07K 2319/33 fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: G01N 2333/315 from Streptococcus (G), e.g. Enterococci
• CPC Class Codes: G01N 33/56911 Bacteria

Abstract

In certain embodiments, novel targeting peptides that specifically/preferentially bind to S. mutans are provided. The targeting peptides can be attached to effectors (e.g., detectable labels, drugs, antimicrobial peptides, etc.) to form chimeric constructs for specifically/preferentially delivering the effector to and/or into the target organism. In certain embodiments the targeting peptides attached, e.g., to antimicrobial peptides can be used to selectively inhibit and/or kill S. mutans and, when used in the oral cavity of a mammal, can be effective to reduce the incidence and/or severity of dental caries and/or the incidence and/or severity of periodontal disease.

Claims

1. A targeting peptide that binds to Streptococcus mutans, where said peptide comprises or consists of the amino acid sequence

X¹-X²-F-R-X⁵-X⁶-X⁷-R-X⁹-X¹⁰-X¹¹-X¹²-X¹³-X¹⁴-X¹⁵-X¹⁶

or the inverse of said amino acid sequence, wherein:

X¹ is a polar amino acid, or A;

X² is F, W, Q, A, or an analog thereof;

X⁵ is a hydrophobic amino acid;

X⁶ is a hydrophobic amino acid, N, Q, or an analog thereof;

X⁷ is a polar amino acid, A, F, or an analog thereof;

X⁹ is a polar amino acid, A or an analog thereof;

X¹⁰ is a hydrophobic amino acid, Q, A, or an analog thereof;

X¹¹ is a hydrophobic amino acid;

X¹² is Q, A, or an analog thereof;

X¹³ is a non-polar amino acid;

X¹⁴ is a hydrophobic amino acid;

X¹⁵ is a non-polar amino acid, N, S, D, or an analog thereof;

X¹⁶ is a polar amino acid, F, A, or an analog thereof; and

said peptide ranges in length up to 100 amino acids.

2. The peptide of claim 1, wherein:

X¹ is A or T;

X² is F, W, Q, or A;

X⁵ is L, or A;

X⁶ is F, L, N, A, or Q;

X⁷ is A, or F;

X⁹ is S or A;

X¹⁰ is Q, or A;

X¹¹ is T, or A;

X¹² is Q or A;

X¹³ is P, or A;

X¹⁴ is L, or A;

X¹⁵ N, S, or D; and

X¹⁶ is K, or Q.

4. The peptide of claim 2, wherein X² is F.

6. The peptide of claim 2, wherein X⁵ is L.

14. The peptide of claim 2, wherein X⁷ is N.

17. The peptide of claim 2, wherein X⁹ is S.

21. The peptide of claim 2, wherein X¹⁰ is F.

23. The peptide of claim 2, wherein X¹¹ is T.

25. The peptide of claim 2, wherein X¹² is Q.

27. The peptide of claim 2, wherein X¹³ is A.

29. The peptide of claim 2, wherein X¹⁴ is L.

32. The peptide of claim 2, wherein X¹⁵ is G, or A.

36. The peptide of claim 2, wherein X¹⁶ is K.

37. The peptide of claim 1, wherein said peptide does not comprise the amino acid sequence TFFRLFNRSFTQALGK.

38. The peptide of claim 1, wherein said peptide comprises or consists of an amino acid sequence selected from the group consisting of AFFRAFNRAFAQALAK (SEQ ID NO:

5), TFFRAFARAFAQAAAK (SEQ ID NO;

6), AFFRAFARAFAQALAK (SEQ ID NO;

7), AFFRLFARAFAQAAAK (SEQ ID NO;

8), TLFRLLNRSLTQALGK (SEQ ID NO;

9), TFFRLFNRSFTQALFK (SEQ ID NO;

10), TFFRLFNRSLTQALGK (SEQ ID NO;

11), TFFRLFNRSFTQALNK (SEQ ID NO;

12), AFFRAFARAFAQAAAK (SEQ ID NO;

13), AFFRAFNRAFAQAAAK (SEQ ID NO;

14), TFFRLFNRSFTQALSK (SEQ ID NO;

15), AFFRAFARSFAQAAAK (SEQ ID NO;

16), AFFRAFARAFAQAAGK (SEQ ID NO;

17), AFFRAFARAFTQAAAK (SEQ ID NO;

18), TFFRLFNRSFTQALGQ (SEQ ID NO;

19), TFFRLLNRSFTQALGK (SEQ ID NO;

20), TWFRLFNRSFTQALGK (SEQ ID NO;

21), AFFRAFARAFAQAFAK (SEQ ID NO;

22), TQFRLFNRSFTQALGK (SEQ ID NO;

23), TFFRLFNRSFTQALDK (SEQ ID NO;

24), TFFRLFNRSFTQALAK (SEQ ID NO;

25), TFFRLFNRSFTQALGE (SEQ ID NO;

26), TFFRLFSRSFTQALGK (SEQ ID NO;

27), TFFRLFNRSFTQALGA (SEQ ID NO;

28), TFFRLFDRSFTQALGK (SEQ ID NO;

29), TFFRLFNRSFTQALGF (SEQ ID NO;

30), TFFRAFARSFTQAAAK (SEQ ID NO;

31), TFFRLFARSFTQAAGK (SEQ ID NO;

32), TFFRLFNRSFTQ L K (SEQ ID NO;

33), TFFRLFNRSFTQALGS (SEQ ID NO;

34), TLFRLFNRSFTQALGK (SEQ ID NO;

35), TFFRLNFRSFTQALGK (SEQ ID NO;

36), TFFRLFNRSQTQALGK (SEQ ID NO;

37), TFFRLFAAAFTQALGK (SEQ ID NO;

38), TFFRLFNRSFTQALGK (SEQ ID NO;

39), TFFRLFNRSAAAALGK (SEQ ID NO;

40), TFFRLFFRSNTQALGK (SEQ ID NO;

41), TFFRLFNRSFTQPLGK (SEQ ID NO;

42), TAFRLANRSATQALGK (SEQ ID NO;

43), TFFRLFNRSFTQAAAA (SEQ ID NO;

44), TFFRLQNRSFTQALGK (SEQ ID NO;

45), TFFRLFNRSFTQALPK (SEQ ID NO;

46), TYYRLFNRSFTQALGK (SEQ ID NO;

47), TFFRLF RSFTQALGK (SEQ ID NO;

48), and TQFRLQNRSQTQALGK (SEQ ID NO;

49).

45. The of claim 1, wherein said peptide is attached to an effector moiety selected from the group consisting of a detectable label, a porphyrin or other photosensitizer, an antimicrobial peptide, an antibiotic, a ligand, a lipid or liposome, an agent that physically disrupts the extracellular matrix within a community of microorganisms, and a polymeric particle.

46. The peptide of claim 45, wherein said peptide is attached to an antimicrobial peptide.

48. The peptide of claim 46, wherein said peptide is attached to an antimicrobial peptide comprising or consisting of an amino acid sequence selected from the group consisting of G2 KNLRIIRKGIHIIKKY* (SEQ ID NO:

2), Novispirin G10 KNLRRIIRKGIHIIKKYG (SEQ ID NO;

49), Novispirin T10 KNLRRIIRKTIHIIKKYG (SEQ ID NO;

50), Novispirin G7 KNLRRIGRKIIHIIKKYG (SEQ ID NO;

51), Novispirin T7 KNLRRITRKIIHIIKKYG (SEQ ID NO;

52), Ovispirin KNLRRIIRKIIHIIKKYG (SEQ ID NO;

53), PGG GLLRRLRKKIGEIFKKYG (SEQ ID NO;

54), Protegrin-1 RGGRLCYCRRRFCVCVGR* (SEQ ID NO;

55), K-1 GLGRVIGRLIKQIIWRR (SEQ ID NO;

56), K-2 VYRKRKSILKIYAKLKGWH (SEQ ID NO;

57), K-7 NYRLVNAIFSKIFKKKFIKF (SEQ ID NO;

58), K-8 KILKFLFKKVF (SEQ ID NO;

59), K-9 FIRKFLKKWLL (SEQ ID NO;

60), K-10 KLFKFLRKHLL (SEQ ID NO;

61), K-11 KILKFLFKQVF (SEQ ID NO;

62), K-12 KILKKLFKFVF (SEQ ID NO;

63), K-13 GILKKLFTKVF (SEQ ID NO;

64), K-14 LRKFLHKLF (SEQ ID NO;

65), K-15 LRKNLRWLF (SEQ ID NO;

66), K-16 FIRKFLQKLHL (SEQ ID NO;

67), K-17 FTRKFLKFLHL (SEQ ID NO;

68), K-18 KKFKKFKVLKIL (SEQ ID NO;

69), K-19 LLKLLKLKKLKF (SEQ ID NO;

70), K-20 FLKFLKKFFKKLKY (SEQ ID NO;

71), K-21 GWLKMFKKIIGKFGKF (SEQ ID NO;

72), K-22 GIFKKFVKILYKVQKL (SEQ ID NO;

73), and B-33 FKKFWKWFRRF (SEQ ID NO;

107).

75. A pharmaceutical composition comprising a peptide of claim 1 attached to an antimicrobial peptide in a pharmaceutically acceptable carrier.

78. A method of killing or inhibiting the growth or proliferation of a bacterium, said method comprising:

contacting said bacterium or a biofilm comprising said bacterium with a composition comprising a targeting peptide of claim 1 attached to an antimicrobial peptide, and/or to an antibiotic, and/or to a porphyrin or other photosensitizer.

79. A method of reducing or preventing the formation of dental caries and/or the incidence or severity of periodontal disease in a mammal, said method comprising:

administering to the oral cavity of said mammal a composition comprising a targeting peptide of claim 1 attached to an antimicrobial peptide, and/or to an antibiotic, and/or to a porphyrin or other photosensitizer.

89. A method of detecting a bacterium and/or a bacterial film, said method comprising:

contacting said bacterium or bacterial film with a composition comprising a targeting peptide of claim 1 attached to a detectable label; and

detecting said detectable label wherein the quantity and/or location of said detectable label is an indicator of the presence of said bacterium and/or bacterial film.

91. A composition comprising a targeting peptide of claim 1 attached to a photosensitizing agent.

96. A method of inhibiting the growth or proliferation of a microorganism or a biofilm, said method comprising contacting said microorganism or biofilm with a composition comprising a targeting peptide of claim 1 attached to a photosensitizing agent.

97. A method of reducing or preventing the formation of dental caries and/or the incidence or severity of periodontal disease in a mammal, said method comprising:

administering to the oral cavity of said mammal a composition comprising a targeting peptide of claim 1 attached to a photosensitizing agent.

3. (canceled)

9. The peptide of claim 3, wherein X⁶ is F.

5. (canceled)

7-8. -8. (canceled)

10-13. -13. (canceled)

15-16. -16. (canceled)

18-20. -20. (canceled)

22. (canceled)

24. (canceled)

26. (canceled)

28. (canceled)

30-31. -31. (canceled)

33-35. -35. (canceled)

39-44. -44. (canceled)

47. (canceled)

49-66. -66. (canceled)

67. An antimicrobial peptide that ranges in length up to 100 amino acids, where said peptide comprises or consists of an amino acid sequence selected from the group consisting of FIGAIARLLSKIFGKR (SEQ ID NO:

228), GIFSKLAGKKIKNLLISG (SEQ ID NO;

229), GIFSKLAGKKIKNLLISGLKG (SEQ ID NO;

230), GLFSKFVGKGIKNFLIKGVK (SEQ ID NO;

231), KAYSTPRCKGLFRALMCWL (SEQ ID NO;

232), KIFGAIWPLALGALKNLIK (SEQ ID NO;

233), GWGSFFKKAAHVGKHVGKAALTHYL (SEQ ID NO;

234), RGLRRLGRKIAHGVKKYG (SEQ ID NO;

235), RGLRRLGRKIAHGVKKYGPTVLRIIRIAG (SEQ ID NO;

236), KIAHGVKKYGPTVLRIIR (SEQ ID NO;

237), LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES (SEQ ID NO;

238), FLPLIGRVLSGIL (SEQ ID NO;

239), IGKFLKKAKKFGKAFVKILKK (SEQ ID NO;

240), GKFLKKAKKFGKAFVKIL (SEQ ID NO;

241), WFLKFLKKFFKKLKY (SEQ ID NO;

242), RGLRRLGRKIAHGVKKY (SEQ ID NO;

243), LLGDFFRKSKEKI (SEQ ID NO;

244), and ILRWPWWPWRRK (SEQ ID NO;

245).

68-74. -74. (canceled)

76-77. -77. (canceled)

80-88. -88. (canceled)

90. (canceled)

92-95. -95. (canceled)

98-102. -102. (canceled)