COMBINATORIAL SYNTHESIS AND BIOMARKER DEVELOPMENT

• US 20190113521A1
• Filed: 03/21/2017
• Published: 04/18/2019
• Est. Priority Date: 03/25/2016
• Status: Active Grant

• Current Assignee: Ten30 Biosciences Incorporated
• Original Assignee: Muralidhar Reddy Moola
• Inventors: Moola, Muralidhar Reddy
• Granted Patent: US 10,458,995 B2
• Time in Patent Office: Days
• CPC Class Codes: 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
• CPC Class Codes: B01J 19/0046 Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays synthesis methods per se C40B50/00
• CPC Class Codes: B01J 2219/00648 by the use of solid beads
• CPC Class Codes: B01J 2219/00725 Peptides
• CPC Class Codes: C07K 1/047 Simultaneous synthesis of different peptide species; Peptide libraries
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C40B 30/04 by measuring the ability to specifically bind a target molecule, e.g. antibody-antigen binding, receptor-ligand binding
• CPC Class Codes: G01N 2500/04 Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
• CPC Class Codes: G01N 2800/2814 Dementia; Cognitive disorders
• CPC Class Codes: G01N 2800/2821 Alzheimer
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/60 Complex ways of combining multiple protein biomarkers for diagnosis
• CPC Class Codes: G01N 33/6854 Immunoglobulins
• CPC Class Codes: G01N 33/6896 Neurological disorders, e.g. Alzheimer's disease

Abstract

Provided herein are methods, kits, and compositions for use in the diagnosis and treatment of diseases. Peptoids recognized by Alzheimer s disease specific antibodies are identified.

Claims

1. A method comprising

a. contacting a sample with one or more peptoid or pharmaceutically acceptable salt thereof, wherein said one or more peptoid or pharmaceutically acceptable salt thereof is capable of binding at least two antibody subtypes or fragments thereof;

and

b. using a computer system to detect whether or not a molecule is bound to said one or more peptoid or pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein said one or more peptoid or pharmaceutically acceptable salt thereof comprises said peptoid as described in claim 84.

3. The method of claim 1 or 2, wherein said at least two antibody subtypes comprises at least one of an IgG, IgM, IgD, IgE or an IgA.

27. The method of any one of claims 1-26, wherein said sample is tissue, cell, urine, serum, whole blood, cerebrospinal fluid, sputum, saliva, or semen.

28. The method of claim 27, wherein said sample is serum.

29. The method of claim 27 or 28, wherein said sample is obtained from a mammal.

30. The method of claim 29, wherein said mammal is a human subject.

31. The method of claim 30, wherein said subject is suspected of having a disease.

32. The method of claim 31, wherein said disease is a neurological disease.

33. The method of claim 32, wherein said neurological disease is Parkinson'"'"'s disease.

34. The method of claim 32, wherein said neurological disease is Alzheimer'"'"'s disease.

35. The method of any one of claims 1-34, wherein the detecting utilizes a method comprising radio immunoassay (“

RIA”

), fluorescence immunoassay (“

FIA”

), enzyme-linked immunosorbent assay (“

ELISA”

), western blot, flow cytometry, Forster resonance energy transfer (“

FRET”

), surface plasmon resonance, or any combination thereof.

36. The method of claim 35, further comprising communicating a result of whether or not said one or more peptoid or pharmaceutically acceptable salt thereof is bound to said molecule through a communication medium.

37. The method of claim 36, wherein said communication medium comprises an electronic medium.

38. The method of claim 37, wherein said electronic medium comprises a device comprising a processor or a microprocessor.

39. The method of claim 1, 4 or 35, wherein said molecule is a biomarker.

40. The method of claim 39, further comprising identifying said biomarker.

41. The method of claim 39, wherein said one or more peptoid or pharmaceutically acceptable salt thereof has a binding affinity of at least 10⁻

5 M (K_D) for said biomarker.

42. The method of claim 39, wherein said biomarker is a peptide, a protein, a carbohydrate, a lipid, a lipoprotein, a receptor, a T cell receptor, a molecule with a molecular weight of 1000 Daltons or less, a cell, an antibody or a fragment thereof.

43. The method of claim 42, wherein said biomarker is an antibody or a fragment thereof.

44. The method of claim 43, wherein said antibody is an IgG, IgM, or an IgA, a fragment thereof or any combination thereof.

45. The method of claim 44, wherein said antibody is an IgM or a fragment thereof.

46. The method of claim 44, wherein said antibody is an IgA or a fragment thereof.

47. The method of claim 1 or 4 wherein said one or more peptoid or pharmaceutically acceptable salt thereof comprise integrated therein about 9, 10, 11, 12, 13 or more monomers that can be different or the same.

48. The method of any one of claims 1-47, wherein said one or more peptoid or pharmaceutically acceptable salt thereof is associated with a support.

49. The method of claim 48, wherein said one or more peptoid or pharmaceutically acceptable salt thereof is bound to said support.

50. The method of claim 49, wherein said one or more peptoid or pharmaceutically acceptable salt thereof is covalently bound to said support.

51. The method of claim 49, wherein said one or more peptoid or pharmaceutically acceptable salt thereof is non-covalently bound to said support.

52. The method of claim 48, wherein there is a linker between said support and said one or more peptoid or pharmaceutically acceptable salt thereof.

53. The method of claim 52, wherein said linker is covalently bound to said support.

54. The method of claim 52, wherein said linker is non-covalently bound to said support.

55. The method of claim 52, wherein said linker comprises a polyethylene glycol (“

PEG”

) linker.

56. The method of claim 55, wherein said linker comprises integrated therein a positive amount of less than or equal to about 10 PEG monomeric units.

57. The method of any one of claims 48-56 wherein said support is a solid support.

58. The method of claim 57, wherein said solid support is a glass slide, silicon surface, bead, resin or an array.

59. The method of claim 58, wherein said solid support is a bead.

60. The method of claim 58, wherein said solid support is a resin.

61. The method of claim 58, wherein said solid support is an array.

62. The method of claim 57, wherein said solid support is associated with a brush polymer.

63. The method of claim 57, wherein said solid support is associated with a bottle brush polymer.

64. The method of claim 39, wherein said biomarker indicates a subject'"'"'s likelihood of having a disease.

65. The method of claim 64, wherein said disease is a neurological disease, cancer, autoimmune disease or an infectious disease.

66. The method of claim 65, wherein said disease is a neurological disease.

67. The method of claim 65, wherein said neurological disease is Parkinson'"'"'s disease.

68. The method of claim 65, wherein said neurological disease is Alzheimer'"'"'s disease.

69. The method of claim 64, wherein there is a likelihood of said disease if said biomarker is bound to said one or more peptoid or pharmaceutically acceptable salt thereof.

70. The method of claim 69, wherein said likelihood of said disease is indicated by a second test.

71. The method of claim 64, further comprising diagnosing said disease if said biomarker is bound to said one or more peptoid or pharmaceutically acceptable salt thereof.

72. The method of claim 64, further comprising diagnosing said disease if said biomarker is bound to said one or more peptoid or pharmaceutically acceptable salt thereof and is above a concentration that is observed in a control non diseased subject sample.

73. The method of claim 64, further comprising diagnosing said disease if said biomarker is bound to said one or more peptoid or pharmaceutically acceptable salt thereof and is below a concentration that is observed in a control non diseased subject sample.

74. The method of any one of claims 71-73, further comprising administering a treatment for said disease.

75. The method of claim 1 or 4, further comprising repeating (a) and (b) at different time points to monitor a disease.

76. The method of claim 75, wherein said different time points are within 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 8 months or 1 year.

77. The method of claim 75, wherein said repeating (a) and (b) is performed following the administration of a treatment to a subject.

78. The method of claim 77, wherein said detecting of said biomarker is determinative of said subject'"'"'s response to said treatment.

79. The method of claim 39, wherein said detecting of said biomarker is determinative at least in part for whether a subject is eligible for a clinical trial.

80. The method of claim 39, wherein said biomarker determines a likelihood of a subject having an adverse reaction to a drug.

105. A method for preventing, treating, ameliorating or managing a disease or condition which comprises administering to a patient in need of such prevention, treatment, amelioration or management, a prophylactically or therapeutically effective amount of a prophylactically or therapeutically acceptable amount of said biomarker of claim 39 or 82, wherein said biomarker is present in a subsect free from said disease and an absence of said biomarker is indicative of said disease.

4. A method comprising;

a. contacting a sample with one or more peptoid or pharmaceutically acceptable salt thereof, wherein said one or more peptoid or pharmaceutically acceptable salt thereof comprises a compound of formula I;

5. The method of claim 4, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is selected from the group consisting of deuterium and hydrogen.

6. The method of claim 4 or 5, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₂ is selected from the group consisting of piperonyl;

cyclopropyl;

dimethoxybenzyl;

morpholyl;

aminobutyl; and

pyridyl.

7. The method of any one of claims 4-6, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₃ is selected from the group consisting of allyl;

methylbenzyl;

cyclopropyl;

diphenylethyl;

benzyl;

dimethoxybenzyl; and

methyl.

8. The method of any one of claims 4-7, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₄ is selected from the group consisting of benzyl;

isobutyl;

cyclopropyl;

piperonyl; and

aminobutyl.

9. The method of any one of claims 4-8, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₅ is selected from the group consisting of benzyl;

aminobutyl;

isobutyl;

diphenylethyl; and

methyl.

10. The method of any one of claims 4-9, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₆ is selected from the group consisting of diphenylethyl;

aminobutyl;

or methylbenzyl.

11. The method of any one of claims 4-10, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₇ is selected from the group consisting of methyl;

methylbenzyl;

piperonyl;

diphenylethyl;

aminobutyl.

12. The method of any one of claims 4-11, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₈ is selected from the group consisting of pyridyl;

allyl;

piperonyl;

aminobutyl;

isobutyl;

diphenylethyl;

or benzyl.

13. The method of any one of claims 4-12, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₉ is selected from the group consisting of methylbenzyl;

benzyl;

diphenylethyl;

aminobutyl.

14. The method of any one of claims 4-13, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁₀ is selected from the group consisting of methyl;

aminobutyl;

benzyl;

piperonyl;

isobutyl.

15. The method of any one of claims 4-14, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁₁ is selected from the group consisting of hydrogen and deuterium.

16. The method of any one of claims 4-15, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁₂ is selected from the group consisting of hydrogen and deuterium.

17. The method of any one of claims 4-16, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁₃ is selected from the group consisting of hydrogen and deuterium.

18. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is piperonyl;

R₃ is dimethoxybenzyl;

R₄ is benzyl;

R₅ is benzyl;

R₆ is diphenylethyl;

R₇ is methyl;

R₈ is pyridyl;

R₉ is methylbenzyl;

R₁₀ is benzyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

19. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is cyclopropyl;

R₃ is allyl;

R₄ is isobutyl;

R₅ is aminobutyl;

R₆ is diphenylethyl;

R₇ is methylbenzyl;

R₈ is benzyl;

R₉ is benzyl;

R₁₀ is methyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

20. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is dimethoxybenzyl;

R₃ is methylbenzyl;

R₄ is cyclopropyl;

R₅ is isobutyl;

R₆ is methylbenzyl;

R₇ is piperonyl;

R₈ is allyl;

R₉ is diphenylethyl;

R₁₀ is benzyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

21. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is morpholyl;

R₃ is cyclopropyl;

R₄ is piperonyl;

R₅ is diphenylethyl;

R₆ is aminobutyl;

R₇ is aminobutyl;

R₈ is benzyl;

R₉ is benzyl;

R₁₀ is aminobutyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

22. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is dimethoxybenzyl;

R₃ is diphenylethyl;

R₄ is aminobutyl;

R₅ is methyl;

R₆ is diphenylethyl;

R₇ is methylbenzyl;

R₈ is piperonyl;

R₉ is methylbenzyl;

R₁₀ is benzyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

23. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is aminobutyl;

R₃ is benzyl;

R₄ is aminobutyl;

R₅ is aminobutyl;

R₆ is aminobutyl;

R₇ is diphenylethyl;

R₈ is aminobutyl;

R₉ is aminobutyl;

R₁₀ is morpholyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

24. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is dimethoxybenzyl;

R₃ is dimethoxybenzyl;

R₄ is aminobutyl;

R₅ is aminobutyl;

R₆ is methylbenzyl;

R₇ is methyl;

R₈ is isobutyl;

R₉ is benzyl;

R₁₀ is piperonyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

25. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is pyridyl;

R₃ is methyl;

R₄ is cyclopropyl;

R₅ is isobutyl;

R₆ is aminobutyl;

R₇ is aminobutyl;

R₈ is diphenylethyl;

R₉ is aminobutyl;

R₁₀ is isobutyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

26. The method of any one of claims 4-17, wherein, in said one or more peptoid or pharmaceutically acceptable salt thereof of formula I, R₁ is hydrogen or deuterium;

R₂ is dimethoxybenzyl;

R₃ is cyclopropyl;

R₄ is benzyl;

R₅ is isobutyl;

R₆ is aminobutyl;

R₇ is aminobutyl;

R₈ is benzyl;

R₉ is benzyl;

R₁₀ is isobutyl;

R₁₁, R₁₂ and R₁₃ are each independently selected from hydrogen or deuterium.

82. A method of screening for a biomarker comprising:

a. contacting a control sample with a support having at one or more peptoid or pharmaceutically acceptable salt thereof associated with said support, wherein said one or more peptoid or pharmaceutically acceptable salt thereof have a formula as claimed in claim 4;

b. contacting said support with a disease sample; and

c. detecting said biomarker wherein said biomarker is bound to said one or more peptoid or pharmaceutically acceptable salt thereof and said biomarker is not present in said control sample or said one or more peptoid or pharmaceutically acceptable salt thereof does not bind to said biomarker in said control sample.

83. A method comprising:

a. contacting one or more peptoid or pharmaceutically acceptable salt thereof with a support having at least one biomarker associated with said support, wherein said one or more peptoid or pharmaceutically acceptable salt thereof have a formula as claimed in claim 4; and

b. detecting said biomarker having said one or more peptoid or pharmaceutically acceptable salt thereof bound thereto.

85. The method of any one of claims 4, or 81-83 wherein said one or more peptoid or pharmaceutically acceptable salt thereof is selected from a group comprising a formula:

100. The kit of claim 99, wherein said peptoid or pharmaceutically acceptable salt thereof is selected from a group comprising a formula as claimed in claim 85.

81. A method comprising:

a. contacting a sample with a non-random peptoid library, wherein said non-random peptoid library comprises one or more peptoid or pharmaceutically acceptable salt thereof having an affinity to an antibody, wherein said antibody comprises an IgA or a fragment thereof, or an IgM or a fragment thereof; and

b. detecting whether said antibody is bound to said one or more peptoid or pharmaceutically acceptable salt thereof.

84. A peptoid or pharmaceutically acceptable salt thereof comprising a compound of formula I:

86. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

87. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

88. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

89. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

90. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

91. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

92. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

93. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

94. A peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising a structure

95. A method of making an array comprising associating said peptoid or pharmaceutically acceptable salt thereof of claim 84 with a support.

96. A method of synthesizing said peptoid or pharmaceutically acceptable salt thereof of claim 84 in association with a support.

97. A method of making said peptoid or pharmaceutically acceptable salt thereof of claim 84 comprising coupling one or more monomers to form said peptoid or pharmaceutically acceptable salt thereof.

98. The method of claim 97, wherein each of said one or monomers is independently selected from one of a Benzylamine, Methylamine, Allylamine, Isobutulamine, 4-(Aminomethyl)pyridine, 4-(2-Aminoethyl)morpholine, 3,4-Dimethoxybenzylamine, 2,2-Diphenylethylamine, Piperonylamine, R-(+)-α

-Methylbenzylamine, Cyclopropylamine, 1,4-Diaminobutane, or Glycine, or 2-Aminoethanol.

99. A kit comprising a peptoid or pharmaceutically acceptable salt thereof comprising a formula as claimed in claim 84.

101. A composition comprising said peptoid or pharmaceutically acceptable salt thereof of claim 84.

102. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and said peptoid or pharmaceutically acceptable salt thereof of claim 101.

103. The pharmaceutical composition of claim 102, wherein said carrier is a parenteral carrier, oral or topical carrier.

104. A method for preventing, treating, ameliorating or managing a disease or condition which comprises administering to a patient in need of such prevention, treatment, amelioration or management, a prophylactically or therapeutically effective amount of a prophylactically or therapeutically acceptable amount of said peptoid or pharmaceutically acceptable salt thereof of claim 84.

106. The method of claim 104 or 105, wherein said disease or condition is a neurological disease, cancer, autoimmune disease or an infectious disease.

107. The method of claim 106, wherein said disease is a neurological disease.

108. The method of claim 107, wherein said neurological diseases is Parkinson'"'"'s disease or Alzheimer'"'"'s disease.

109. The peptoid or pharmaceutically acceptable salt thereof of claim 84, wherein said peptoid or pharmaceutically acceptable salt thereof is selected from a group comprising a formula: