US2008242614A1PendingUtilityA1
Compositions and methods for treating infections using analogues of indolicidin
Est. expiryAug 21, 2016(expired)· nominal 20-yr term from priority
C07K 7/08A61K 41/0028A61P 31/10A61K 38/00A61P 31/04A61P 31/12A61P 31/00C07K 14/001A61K 47/60A61P 33/00Y02A50/30
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Claims
Abstract
Compositions and methods for treating infections, especially bacterial infections, are provided. Indolicidin peptide analogues containing at least two basic amino acids are prepared. The analogues are administered as modified peptides, preferably containing photo-oxidized solubilizer.
Claims
exact text as granted — not AI-modified1 . A method for preventing a microbial infection, comprising administering to a patient a therapeutically effective amount of a composition comprising at least one indolidicin analogue of up to 35 amino acids that comprises one of the following sequences:
(SEQ ID NO: 33)
Ile Leu Lys Lys Trp Pro Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 34)
Ile Leu Lys Lys Tyr Pro Trp Tyr Pro Trp Arg Arg
Lys;
(SEQ ID NO: 40)
Ile Leu Lys Trp Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 42)
Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 44)
Ile Leu Trp Pro Trp Trp Pro Arg Arg Lys;
(SEQ ID NO: 46)
Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys
Ile Met Ile Leu Lys Lys Ala Gly Ser;
(SEQ ID NO: 47)
Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys
Met Ile Leu Lys Lys Ala Gly Ser;
(SEQ ID NO: 48)
Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys
Asp Met Ile Leu Lys Lys Ala Gly Ser;
(SEQ ID NO: 52)
Leu Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 55)
Ile Leu Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg
Met Ile Leu Lys Lys Ala Gly Ser;
(SEQ ID NO: 56)
Ile Leu Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg
Ile Met Ile Leu Lys Lys Ala Gly Ser;
(SEQ ID NO: 58)
Ile Leu Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg
Met;
(SEQ ID NO: 59)
Ile Leu Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg
Ile Met;
(SEQ ID NO: 60)
Ile Leu Lys Lys Trp Trp Trp Pro Trp Arg Lys;
(SEQ ID NO: 61)
Ile Leu Lys Lys Trp Pro Trp Trp Trp Arg Lys;
(SEQ ID NO: 65)
Ile Leu Lys Lys Trp Val Trp Trp Val Trp Arg Arg
Lys;
(SEQ ID NO: 66)
Ile Leu Lys Lys Trp Pro Trp Trp Val Trp Arg Arg
Lys;
(SEQ ID NO: 67)
Ile Leu Lys Lys Trp Val Trp Trp Pro Trp Arg Arg
Lys;
(SEQ ID NO: 69)
Ile Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 70)
Ile Leu Lys Lys Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 71)
Ile Leu Lys Lys Trp Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 72)
Ile Leu Lys Lys Trp Pro Trp Trp Trp Arg Arg Lys;
(SEQ ID NO: 73)
Ile Leu Lys Lys Trp Pro Trp Trp Pro Arg Arg Lys;
(SEQ ID NO: 76)
Ala Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 77)
Ile Ala Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 78)
Ile Leu Ala Trp Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 79)
Ile Leu Arg Ala Pro Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 80)
Ile Leu Arg Trp Ala Trp Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 81)
Ile Leu Arg Trp Pro Ala Trp Pro Trp Arg Arg Lys;
(SEQ ID NO: 82)
Ile Leu Arg Trp Pro Trp Ala Pro Trp Arg Arg Lys;
(SEQ ID NO: 31)
Lys Arg Arg Trp Pro Trp Trp Pro Trp Lys Lys Leu
Ile;
(SEQ ID NO: 43)
Lys Arg Arg Trp Pro Trp Trp Pro Trp Arg Leu Ile;
(SEQ ID NO: 54)
Ile Leu Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg
Lys Met Ile Leu Lys Lys Ala Gly Ser;
(SEQ ID NO: 57)
Ile Leu Lys Lys Trp Pro Trp Trp Pro Trp Arg Arg
Lys Met;
(SEQ ID NO: 26)
Trp Arg Ile Trp Lys Pro Lys Trp Arg Leu Pro Lys
Trp;
(SEQ ID NO: 27)
Ile Leu Arg Trp Val Trp Trp Val Trp Arg Arg Lys;
(SEQ ID NO: 68)
Lys Arg Arg Trp Val Trp Trp Val Trp Arg Leu Ile;
(SEQ ID NO: 83)
Ile Leu Arg Trp Pro Trp Trp Ala Trp Arg Arg Lys;
(SEQ ID NO: 84)
Ile Leu Arg Trp Pro Trp Trp Pro Ala Arg Arg Lys;
(SEQ ID NO: 85)
Ile Leu Arg Trp Pro Trp Trp Pro Trp Ala Arg Lys;
(SEQ ID NO: 86)
Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Ala Lys;
or
(SEQ ID NO: 87)
Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Ala.
2 . The method of claim 1 , wherein at least one analogue has one or more amino acids altered to a corresponding D-amino acid.
3 . The method of claim 1 , wherein the N-terminal and/or C-terminal amino acid of at least one analogue is a D-amino acid.
4 . The method of claim 1 , wherein at least one analogue is acetylated at the N-terminal amino acid.
5 . The method of claim 1 , wherein at least one analogue is amidated at the C-terminal amino acid.
6 . The method of claim 1 , wherein at least one analogue is esterified at the C-terminal amino acid.
7 . The method of claim 1 , wherein at least one analogue is modified by incorporation of homoserine/homoserine lactone at the C-terminal amino acid.
8 . The method of claim 1 , wherein the composition is incorporated in a liposome or a slow-release vehicle.
9 . The method of claim 1 , wherein the indolicidin analogue has an amino acid sequence consisting of Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys (SEQ ID NO: 42).
10 . The method of claim 1 , wherein the infection is due to a microorganism selected from the group consisting of a bacterium, a fungus, and a parasite.
11 . The method of claim 10 , wherein the microorganism is a Gram-negative or Gram-positive bacterium.
12 . The method of claim 11 , wherein the Gram-negative bacterium is selected from the group consisting of Enterobacter sp., E. coli and Acinetobacter sp.
13 . The method of claim 11 , wherein the Gram-positive bacterium is selected from the group consisting of S. aureus, coagulase negative staphylococci, S. epidermidis, S. pneumoniae, and Viridans Streptococci.
14 . The method of claim 10 , wherein the fungus is a pathogenic yeast.
15 . The method of claim 10 , wherein the fungus is a mold that causes a wound or device-related infection.
16 . The method of claim 1 , wherein the composition is administered by intravenous injection, intraperitoneal injection or implantation, intramuscular injection or implantation, intrathecal injection, subcutaneous injection or implantation, intradermal injection, lavage, bladder wash-out, suppositories, pessaries, oral ingestion, topical application, enteric application, inhalation, or nasal route.
17 . The method of claim 1 , wherein the composition is administered nasally.
18 . The method of claim 1 , wherein the composition is administered by local application.
19 . The method of claim 1 , wherein the method is for preventing a microbial infection associated with a medical device.
20 . The method of claim 19 , wherein the medical device is a stent, tubing, probe, cannula, catheter, synthetic vascular graft, blood monitoring device, artificial heart valve, or needle.
21 . The method of claim 19 , wherein the medical device is a catheter.
22 . The method of claim 1 , further comprising administering a therapeutically effective amount of an antibiotic.
23 . The method of claim 22 , wherein the antibiotic is selected from the group consisting of minocycline, rifampin, cefazolin, vancomycin, and teicoplanin.
24 . The method of claim 22 , wherein the antibiotic is a beta lactam.
25 . The method of claim 22 , wherein the indolicidin analogue and the antibiotic are in the same composition.
26 . The method of claim 1 , wherein the composition further comprises a physiologically acceptable buffer.
27 . The method of claim 1 , wherein the composition is a gel.
28 . A method for preventing a catheter-related infection comprising administering to a patient a therapeutically effective amount of a composition comprising an indolicidin analogue of up to 35 amino acids comprising the sequence of Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys (SEQ ID NO: 42).
29 . The method of claim 28 , wherein the amino acid sequence consists of Ile Leu Arg Trp Pro Trp Trp Pro Trp Arg Arg Lys (SEQ ID NO: 42).
30 . The method of claim 28 , wherein the composition further comprises a physiologically acceptable buffer.
31 . The method of claim 28 , wherein the infection is due to a Gram-negative or Gram-positive bacterium.
32 . The method of claim 31 , wherein the Gram-negative bacterium is selected from the group consisting of Enterobacter sp., E. coli and Acinetobacter sp.
33 . The method of claim 31 , wherein the Gram-positive bacterium is selected from the group consisting of S. aureus, coagulase negative staphylococci, S. epidermidis, S. pneumoniae, and Viridans Streptococci.
34 . The method of claim 28 , wherein the composition is a gel.Cited by (0)
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