CN112608375A - Novel BH3 mimic peptide analogue for inhibiting PTP1B activity and application thereof - Google Patents
Novel BH3 mimic peptide analogue for inhibiting PTP1B activity and application thereof Download PDFInfo
- Publication number
- CN112608375A CN112608375A CN202011518318.0A CN202011518318A CN112608375A CN 112608375 A CN112608375 A CN 112608375A CN 202011518318 A CN202011518318 A CN 202011518318A CN 112608375 A CN112608375 A CN 112608375A
- Authority
- CN
- China
- Prior art keywords
- novel
- dmf
- mimetic peptide
- ptp1b
- washing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 58
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 title claims abstract description 45
- 230000003278 mimic effect Effects 0.000 title claims abstract description 31
- 230000000694 effects Effects 0.000 title claims abstract description 19
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 14
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 title claims abstract description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 8
- 201000010099 disease Diseases 0.000 claims abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 6
- 150000001413 amino acids Chemical class 0.000 claims abstract description 6
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- 229920001184 polypeptide Polymers 0.000 claims abstract description 5
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 118
- 238000005406 washing Methods 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- 239000011347 resin Substances 0.000 claims description 26
- 229920005989 resin Polymers 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 17
- 125000006239 protecting group Chemical group 0.000 claims description 17
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 15
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000000047 product Substances 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 239000003112 inhibitor Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 239000012071 phase Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 238000010567 reverse phase preparative liquid chromatography Methods 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 230000003213 activating effect Effects 0.000 claims description 3
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 239000007790 solid phase Substances 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004108 freeze drying Methods 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000006166 lysate Substances 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 230000010355 oscillation Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- AAAFQLPJNOITCL-SFHVURJKSA-N 9h-fluoren-9-ylmethyl n-[(2s)-1-oxo-3-phenylpropan-2-yl]carbamate Chemical compound C([C@@H](C=O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 AAAFQLPJNOITCL-SFHVURJKSA-N 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 13
- 238000010532 solid phase synthesis reaction Methods 0.000 abstract description 2
- 238000009509 drug development Methods 0.000 abstract 1
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 description 39
- 239000003153 chemical reaction reagent Substances 0.000 description 14
- CMWYAOXYQATXSI-UHFFFAOYSA-N n,n-dimethylformamide;piperidine Chemical compound CN(C)C=O.C1CCNCC1 CMWYAOXYQATXSI-UHFFFAOYSA-N 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 12
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 8
- 238000011161 development Methods 0.000 description 7
- 206010022489 Insulin Resistance Diseases 0.000 description 4
- 235000021314 Palmitic acid Nutrition 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical group N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 238000012216 screening Methods 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- OTKXCALUHMPIGM-FQEVSTJZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 OTKXCALUHMPIGM-FQEVSTJZSA-N 0.000 description 3
- 102000003746 Insulin Receptor Human genes 0.000 description 3
- 108010001127 Insulin Receptor Proteins 0.000 description 3
- 239000007987 MES buffer Substances 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000003178 anti-diabetic effect Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- QWXZOFZKSQXPDC-NSHDSACASA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](C)C(O)=O)C3=CC=CC=C3C2=C1 QWXZOFZKSQXPDC-NSHDSACASA-N 0.000 description 2
- DVBUCBXGDWWXNY-SFHVURJKSA-N (2s)-5-(diaminomethylideneamino)-2-(9h-fluoren-9-ylmethoxycarbonylamino)pentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C3=CC=CC=C3C2=C1 DVBUCBXGDWWXNY-SFHVURJKSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 208000032005 Spinocerebellar ataxia with axonal neuropathy type 2 Diseases 0.000 description 2
- 230000007131 anti Alzheimer effect Effects 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 208000033361 autosomal recessive with axonal neuropathy 2 spinocerebellar ataxia Diseases 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000002608 insulinlike Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 1
- FODJWPHPWBKDON-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-[(2-methylpropan-2-yl)oxy]-4-oxobutanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(=O)OC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 FODJWPHPWBKDON-IBGZPJMESA-N 0.000 description 1
- CBPJQFCAFFNICX-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](CC(C)C)C(O)=O)C3=CC=CC=C3C2=C1 CBPJQFCAFFNICX-IBGZPJMESA-N 0.000 description 1
- QXVFEIPAZSXRGM-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)C3=CC=CC=C3C2=C1 QXVFEIPAZSXRGM-DJJJIMSYSA-N 0.000 description 1
- ZIIUUSVHCHPIQD-UHFFFAOYSA-N 2,4,6-trimethyl-N-[3-(trifluoromethyl)phenyl]benzenesulfonamide Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)NC1=CC=CC(C(F)(F)F)=C1 ZIIUUSVHCHPIQD-UHFFFAOYSA-N 0.000 description 1
- NDKDFTQNXLHCGO-UHFFFAOYSA-N 2-(9h-fluoren-9-ylmethoxycarbonylamino)acetic acid Chemical compound C1=CC=C2C(COC(=O)NCC(=O)O)C3=CC=CC=C3C2=C1 NDKDFTQNXLHCGO-UHFFFAOYSA-N 0.000 description 1
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 229940124810 Alzheimer's drug Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101100144674 Homo sapiens RNF213 gene Proteins 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 102100028516 Receptor-type tyrosine-protein phosphatase U Human genes 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001516 effect on protein Effects 0.000 description 1
- 238000010799 enzyme reaction rate Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000006686 mitochondrial oxygen consumption Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 229920001469 poly(aryloxy)thionylphosphazene Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- RUYANEADGUFWRJ-UHFFFAOYSA-M sodium;(4-nitrophenyl) hydrogen phosphate Chemical compound [Na+].OP([O-])(=O)OC1=CC=C([N+]([O-])=O)C=C1 RUYANEADGUFWRJ-UHFFFAOYSA-M 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4747—Apoptosis related proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4702—Regulators; Modulating activity
- C07K14/4703—Inhibitors; Suppressors
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y301/00—Hydrolases acting on ester bonds (3.1)
- C12Y301/03—Phosphoric monoester hydrolases (3.1.3)
- C12Y301/03048—Protein-tyrosine-phosphatase (3.1.3.48)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Wood Science & Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Toxicology (AREA)
- Gastroenterology & Hepatology (AREA)
- General Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Hematology (AREA)
- Psychiatry (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- Hospice & Palliative Care (AREA)
- Obesity (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a novel BH3 mimic peptide analogue for inhibiting PTP1B activity and application thereof. The structural formula of the novel BH3 mimetic peptide analogs is shown below:
the mimic peptide compound is derived from a core region of a Bim-BH3 structural domain, and is prepared by a polypeptide solid phase synthesis method, and amino acids in the structure are all natural amino acids. The novel BH3 mimic peptide analogue has remarkable activity of inhibiting PTP1B, and has potential application value in drug development of related diseases taking PTP1B as a target, such as diabetes, cancer, Alzheimer's disease and the like.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a novel BH3 mimic peptide analogue for inhibiting PTP1B activity and application thereof.
Background
Protein tyrosine phosphatase 1B (PTP1B) is closely related to the onset and development of type 2 diabetes and obesity, and is a key negative regulatory protein in the insulin signal transduction pathway. Abnormal overexpression of PTP1B results in decreased insulin sensitivity and development of insulin resistance. The PTP1B inhibitor can block tyrosine phosphorylation of Insulin Receptor (IR) stimulated by insulin, further influence phosphorylation of insulin receptor substrate (IRS-1), enhance insulin-like and insulin sensitivity, effectively improve insulin resistance from the source, reduce blood sugar, and simultaneously has no hypoglycemia adverse reaction of insulin-like drugs. Thus, PTP1B is also a hot target for recent studies of T2DM, and several candidate compounds have entered preclinical and phase I, II trials. Recent research views in recent years have shown that: PTP1B can be a (potential) target for the development of anti-tumor and alzheimer drugs. Some researches find that the overexpression of PTP1B can obviously promote the generation and growth of tumors in mice, and the inhibition of the expression of PTP1B by an inhibitor can produce an anti-tumor effect; the mechanism research finds that PTP1B controls the non-mitochondrial oxygen consumption of cells by regulating RNF213 gene, thereby promoting the survival and growth of tumor cells under the anoxic condition. Thus, PTP1B is considered a target for anti-tumor drugs. In recent years, PTP1B has also been used as a regulation effect in physiological processes related to Alzheimer's disease in the central nervous system, and a strategy for inhibiting PTP1B and further antagonizing harmful physiological processes related to Alzheimer's disease regulated by PTP1B is proposed to research and develop anti-Alzheimer's disease drugs. Therefore, PTP1B has become a potential hot target for developing anti-diabetic, cancer and Alzheimer's disease drugs, and the PTP1B inhibitor is expected to be applied to developing anti-diabetic, cancer and Alzheimer's disease drugs taking PTP1B as a target.
At present, inhibitors of PTP1B mainly include small inorganic molecule compounds, organic compounds and PTP1B inhibitors in natural products. But the selectivity of the inorganic micromolecule compound is very low, and the compound has stronger inhibition on all PTPs; most of organic compounds are screened by organic synthesis and combinatorial chemistry methods, a compound with PTP1B activity inhibition is screened firstly, then a substituent group of the compound is modified, and finally a better PTP1B inhibitor is obtained, and the problems of poor stability, higher charge, overhigh lipophilic coefficient and the like which restrict the drug property exist in the inhibitor; PTP1B inhibitor in natural products is obtained by high-throughput screening of natural products isolated and identified in nature, and although it has high selectivity and activity, the site of action is not well-defined. Therefore, it is necessary to make up for the defects of the existing PTP1B inhibitory molecules and develop a novel PTP1B inhibitor which has novel structure, strong selectivity, low toxicity and high efficiency so as to meet the urgent needs of domestic clinical application.
Disclosure of Invention
The invention provides a novel BH3 mimic peptide analogue for inhibiting PTP1B activity and application thereof. The novel BH3 mimic peptide analogue has remarkable PTP1B inhibition activity, and can be used for preparing drugs for preventing or treating related diseases with PTP1B as a target.
In order to realize the purpose of the invention, the invention adopts the following technical scheme to realize:
the invention provides a novel BH3 mimic peptide analogue for inhibiting PTP1B activity, wherein the structural formula of the novel BH3 mimic peptide analogue is as follows:
wherein R1 is a long-chain carboxylic acid, R2 is COOH, and R3 is a carboxylic acid or polycarboxylic acid with different chain lengths.
Further, R1 is palmitic acid.
Further, the peptide chain of the BH3 mimetic peptide analogues scan-1-scan-11 adopts an Ala-scanning strategy, and the N-terminal protecting group is modified by palmitic acid. Other such compounds have been modified at the N-terminus of the peptide chain with carboxylic or polycarboxylic acids of varying chain length.
Further, the novel BH3 mimetic peptide analogs are specifically:
further, the preparation method of the novel BH3 mimic peptide analogue comprises the following steps:
(1) placing Fmoc-Phe-Wang (scan-11 is Fmoc-Ala-Wang) resin in a manual polypeptide solid phase synthesizer at room temperature, and activating by dichloromethane and dimethylformamide;
(2) adding piperidine/dimethylformamide mixed solution to remove the Fmoc protecting group;
(3) adding 3-4 times of resin molar weight of N-Fmoc protected amino acid or carboxylic acid, HOBT, HBTU and 5-6 times of resin molar weight of DIEA, and carrying out oscillation reaction at room temperature for 2-4 h;
(4) repeating steps (2) and (3) until the synthesis of the whole mimic peptide sequence is completed;
(5) adding the lysate into the product obtained in the step (4), stirring at room temperature, filtering, adding anhydrous ether to precipitate a solid, washing, and drying in vacuum to obtain a crude mimic peptide analogue product;
(6) and purifying the crude product of the peptide analogue by using reverse phase preparative liquid chromatography, collecting a target peak mobile phase solution, removing acetonitrile, and freeze-drying to obtain a flocculent or powdery solid, namely a pure BH3 mimic peptide analogue product.
Further, the lysis solution comprises phenol, water, thioanisole and trifluoroacetic acid.
Further, blowing N after filtering in the step (5)2Excess trifluoroacetic acid was removed.
The invention also provides a medicament or a pharmaceutical composition which takes the novel BH3 mimic peptide analogue as an active ingredient, and comprises any novel BH3 mimic peptide analogue and one or more pharmaceutically acceptable carriers or excipients.
The invention also provides application of the novel BH3 mimic peptide analogue in preparation of an inhibitor for inhibiting PTP1B activity.
The invention also provides application of the novel BH3 mimic peptide analogue in preparation of a medicament for preventing or treating diseases taking PTP1B as a target.
Further, the diseases include diabetes, cancer and alzheimer's disease.
Furthermore, the administration mode of the medicament or the pharmaceutical composition taking the novel BH3 mimic peptide analogue as an active ingredient is oral administration or injection.
Compared with the prior art, the invention has the advantages and the technical effects that:
the invention obtains a novel BimBH3 mimic peptide analogue by a polypeptide solid phase synthesis method, the novel BH3 mimic peptide analogue is derived from a core region of a Bim-BH3 structural domain, and amino acids in the structure are natural amino acids. Experiments prove that the novel BH3 mimic peptide analogue has a remarkable inhibiting effect on protein tyrosine phosphatase 1B (PTP1B), and the obtained mimic peptide analogue has high purity, can be used as an excellent PTP1B inhibitor, and can also be applied to the development of medicaments for related diseases taking PTP1B as a target point, such as diabetes, cancer, Alzheimer's disease and the like. Therefore, the novel BH3 mimic peptide analogue has potential application value and good development prospect.
Drawings
FIGS. 1-18 are dose-inhibitory effect curves for the target protein PTP1B for the mimetics scan-2, scan-3, scan-4, scan-5, scan-6, scan-7, scan-8, scan-11, C13-SM6, C14-SM6, C16 diacid-SM6, C18-SM6, C18 diacid-SM6, C20-SM6, C22-SM6, C20 diacid-SM6, C22 diacid-SM6 and Lila-SM6, respectively.
Detailed Description
The technical solution of the present invention will be described in further detail with reference to specific examples. The methods in the following examples are conventional methods unless otherwise specified.
Example 1
The specific preparation process of the synthetic route taking scan-1 as an example is as follows:
(1) resin activation: weighing corresponding amount of Fmoc-Phe-Wang (scan-11 is Fmoc-Ala-Wang) resin, placing the resin in a manual polypeptide solid phase synthesizer, washing with DCM for 4 times, adding 5ml of DCM for swelling and activating for 3h, washing with DMF for 4 times, adding 20% piperidine DMF for removing Fmoc protecting groups twice (20min +5min), washing with DMF for 4 times for 5ml, washing with DCM for 4 times for 5ml, and detecting with Kaiser's reagent.
(2) Attachment of Phe (F): washing with DMF for 3 times, respectively adding Fmoc-Phe-OH, HBTU, HOBt and DIEA with the molar weight of 3 times of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(3) Link Glu (E): washing with DMF for 3 times, respectively adding Fmoc-Glu (OtBu) -OH, HBTU, HOBt and DIEA with the resin molar amount of 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(4) To Asp (D): the DMF is washed for 3 times, 3 times of resin molar weight of Fmoc-Asp (OtBu) -OH, HBTU, HOBt and 6 times of resin molar weight of DIEA are respectively added and dissolved in 10ml of DMF, the mixture is stirred for reaction at room temperature for 2 hours, the DMF is washed for 4 times, 20% piperidine DMF is added for removing Fmoc protecting groups twice (20min +5min), 5ml of DMF is washed for 4 times, 5ml of DCM is washed for 4 times, and Kaiser's reagent is used for detection.
(5) To Gly (G): washing with DMF for 3 times, respectively adding Fmoc-Gly-OH, HBTU, HOBt and DIEA with the molar weight of 3 times and 6 times of the resin molar weight, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(6) The connection Ile (I): washing with DMF for 3 times, respectively adding Fmoc-Ile-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(7) To Arg (R): washing with DMF for 3 times, adding Fmoc-Arg (mtr) -OH, HBTU, HOBt and DIEA with resin molar amount of 3 times and 6 times respectively, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with DMF for 4 times with 5ml, washing with DCM for 4 times, and detecting with Kaiser's reagent. This step was repeated 1 time.
(8) To Arg (R): washing with DMF for 3 times, adding Fmoc-Arg (mtr) -OH, HBTU, HOBt and DIEA with resin molar amount of 3 times and 6 times respectively, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with DMF for 4 times with 5ml, washing with DCM for 4 times, and detecting with Kaiser's reagent. This step was repeated 1 time.
(9) To Leu (L): washing with DMF for 3 times, respectively adding Fmoc-Leu-OH, HBTU, HOBt and DIEA with the molar weight being 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with DMF for 4 times (5 ml), washing with DCM for 4 times (5 ml), and detecting with Kaiser's reagent.
(10) Link Glu (E): washing with DMF for 3 times, respectively adding Fmoc-Glu (OtBu) -OH, HBTU, HOBt and DIEA with the resin molar amount of 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(11) To Glu (Q): washing with DMF for 3 times, respectively adding Fmoc-Glu (OtBu) -OH, HBTU, HOBt and DIEA with the resin molar amount of 3 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with 5ml DMF for 4 times, washing with 5ml DCM for 4 times, and detecting with Kaiser's reagent.
(12) Connection to Ala (A): washing with DMF for 3 times, respectively adding Fmoc-Ala-OH, HBTU, HOBt and DIEA with resin molar weight of 3 times and 6 times, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with DMF for 4 times with 5ml, washing with DCM for 4 times with 5ml, and detecting with Kaiser's reagent.
(13) Connection to Ala (A): washing with DMF for 3 times, respectively adding Fmoc-Ala-OH, HBTU, HOBt and DIEA with resin molar weight of 3 times and 6 times, dissolving in 10ml of DMF, stirring at room temperature for reaction for 2h, washing with DMF for 4 times, adding 20% piperidine DMF to remove Fmoc protecting groups twice (20min +5min), washing with DMF for 4 times with 5ml, washing with DCM for 4 times with 5ml, and detecting with Kaiser's reagent.
(14) Ligation palmitic acid (Pal): washing with DMF for 3 times, respectively adding palmitic acid, HBTU, HOBt and DIEA with the molar weight being 6 times that of the resin and 10 times that of the resin, dissolving in 10ml of DMF, stirring at room temperature for reaction for 4h, washing with 5ml of DMF for 4 times, washing with 5ml of DCM for 4 times, and detecting with Kaiser's reagent.
(15) Cleavage, side chain protecting group cleavage: adding 250mg phenol, 0.5ml water, 0.5ml thioanisole and 9.0ml trifluoroacetic acid into the product, stirring for 2.5h at room temperature, filtering, and adding N2Blowing off trifluoroacetic acid, adding 30ml cold anhydrous ether, centrifuging at 5000rpm for 5min to obtain white precipitate, washing with cold anhydrous ether for 3 times, and vacuum drying to obtain crude product.
(16) Purifying the crude product by using reversed phase preparative liquid chromatography (RP-HPLC), collecting a target peak mobile phase solution, removing acetonitrile, freezing and drying to obtain a flocculent or powdery solid, namely a pure BH3 mimic peptide analogue product, and carrying out structure confirmation by mass spectrometry and high performance liquid chromatography analysis.
Mass spectral data and HPLC purity analysis data for the 27 BH3 mimetic peptide analogs obtained in the manner described above are shown in table 1.
TABLE 1 Mass Spectrometry data and HPLC purity analysis data for BH3 mimetic peptide analogs
Example 2: determination of protein tyrosine phospholipase 1B (PTP1B) inhibitory Activity
According to the invention, MES buffer solution is adopted as a reaction system, human protein tyrosine phosphatase 1B (PTP1B) is utilized, sodium p-nitrophenylphosphate (pNPP) is taken as a specific substrate, a lead compound SM-6 is selected as a positive control, DMSO is taken as a negative control, a screening model taking a 96-well microplate based on an enzyme reaction rate as a carrier is established, and a PTP1B inhibitor is searched by an enzymology method.
The specific implementation method comprises the following steps: mu.L of pNPP (77mM), 86. mu.L of MES buffer, 4. mu.L of compound (2mM), and 100. mu.L of PTP1B solution (50nM) were sequentially added to a 96-well plate using MES buffer system (25mM, pH6.5), and the total reaction volume was 200. mu.L. Each group of 3 replicates were shaken at 25 ℃ for 1min on a shaker with DMSO as a negative control and sodium orthovanadate (2mM) as a positive control, read every 60s on a microplate reader, and dynamically measured for 5min to determine the change in OD 405 (OD/min). The initial phase reaction rates for each well are linearly related and the slope of the linear portion of the kinetic curve determines the reaction rate of PTP1B, which is indicative of enzyme activity. For the obtained data
The data for each set was analyzed using the t-test. The inhibition rate of the compound on PTP1B is calculated according to the formula:
inhibition ratio (%) - (v)DMSO-vSample(s))/vDMSO×100％
Wherein v isDMSO、vSample(s)The initial average reaction rates of the negative control group and the test compound are expressed respectively
The invention performs primary screening on the PTP1B inhibition rate of the mimic peptide under the concentration of 10 mu mol/L, and performs IC (integrated Circuit) on the compound with the primary screening inhibition rate higher than 70 percent50The results of the assay and inhibition are shown in Table 2.
TABLE 2 results of inhibition of PTP1B activity by the tested peptidomimetic analogs
*: compounds with a preliminary screening inhibition of less than 50% were not IC treated50The measurement of (1).
Statistical processing was performed using GraphPad Prism software to plot the effect curves of the inhibitor amounts, see FIGS. 1-18, and calculated to obtain the IC of the PTP1B inhibitory medium concentrations of the mimetic peptide analogues scan-2, scan-3, scan-4, scan-5, scan-6, scan-7, scan-8, scan-11, C13-SM6, C14-SM6, C16 diacids-SM 6, C18-SM6, C18 diacids-SM 6, C20-SM6, C20 diacids-SM 6, C22-SM6, C22 diacids-SM 6 and Lila-SM650Respectively 91.6nmol/L, 703.0nmol/L, 580.9nmol/L, 1208.0nmol/L, 56.5nmol/L, 45.4nmol/L, 63.7nmol/L, 511.9nmol/L, 835.4nmol/L, 262.7nmol/L, 2875nmol/L, 120.2nmol/L, 384.6nmol/L, 3887nmol/L, 443.5nmol/L, 337.9nmol/L, 199.6nmol/L, 4345 nmol/L.
The test result shows that: the mimic peptide analogue of the invention has obvious inhibition effect on protein tyrosine phosphatase 1B, can be used as an excellent PTP1B inhibitor, and is applied to the development of antidiabetic, antitumor and anti-Alzheimer's disease drugs taking PTP1B as a target, thereby having good development prospect.
The above examples are only intended to illustrate the technical solution of the present invention, but not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions.
Claims (10)
1. A novel BH3 mimetic peptide analog which inhibits PTP1B activity, wherein the novel BH3 mimetic peptide analog has the structural formula:
wherein R1 is long-chain carboxylic acid, R2 is COOH, and R3 is carboxylic acid or polycarboxylic acid with different carbon chain lengths.
2. The novel BH3 mimetic peptide analog of claim 1, wherein the novel BH3 mimetic peptide analog is specifically:
3. the novel BH3 mimetic peptide analog of claim 1, wherein the novel BH3 mimetic peptide analog is prepared by a method comprising the steps of:
(1) placing Fmoc-Phe-Wang resin in a manual polypeptide solid phase synthesizer at room temperature, and activating by using dichloromethane and dimethylformamide;
(2) adding piperidine/dimethylformamide mixed solution to remove the Fmoc protecting group;
(3) adding 3-4 times of resin molar weight of N-Fmoc protected amino acid or carboxylic acid, HOBT, HBTU and 5-6 times of resin molar weight of DIEA, and carrying out oscillation reaction at room temperature for 2-4 h;
(4) repeating steps (2) and (3) until the synthesis of the whole mimic peptide sequence is completed;
(5) adding the lysate into the product obtained in the step (4), stirring at room temperature, filtering, adding anhydrous ether to precipitate a solid, washing, and drying in vacuum to obtain a crude mimic peptide analogue product;
(6) and purifying the crude product of the peptide analogue by using reverse phase preparative liquid chromatography, collecting a target peak mobile phase solution, removing acetonitrile, and freeze-drying to obtain a flocculent or powdery solid, namely a pure BH3 mimic peptide analogue product.
4. The novel BH3 mimetic peptide analogues according to claim 3, wherein said cleavage solution comprises phenol, water, thioanisole, and trifluoroacetic acid.
5. The novel BH3 mimetic peptide analogues according to claim 3, wherein N is blown after filtration in step (5)2Excess trifluoroacetic acid was removed.
6. A medicament or pharmaceutical composition comprising as an active ingredient a novel BH3 mimetic peptide analog of any one of claims 1-5, wherein said medicament or pharmaceutical composition comprises any of said novel BH3 mimetic peptide analogs and one or more pharmaceutically acceptable carriers or excipients.
7. Use of a novel BH3 mimetic peptide analog of any one of claims 1-5 in the preparation of an inhibitor for inhibiting PTP1B activity.
8. Use of a novel BH3 mimetic peptide analog of any one of claims 1-5 in the manufacture of a medicament for the prevention or treatment of PTP 1B-targeted diseases.
9. Use according to claim 8, characterized in that: the diseases include diabetes, cancer and alzheimer's disease.
10. Use according to claim 8, characterized in that: the administration mode of the medicine or the medicine composition taking the novel BH3 mimic peptide analogue as the active ingredient is oral administration or injection.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210966082.XA CN115403664A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof |
| CN202210965782.7A CN115403661A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-G9A and application thereof |
| CN202210965781.2A CN115417922A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-F12A and application thereof |
| CN202011518318.0A CN112608375B (en) | 2020-12-21 | 2020-12-21 | Novel BH3 mimetic peptide analogue for inhibiting PTP1B activity and application thereof |
| CN202210965783.1A CN115403662A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-Q3A and application thereof |
| CN202210965785.0A CN115403663A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-I8A and application thereof |
| PCT/CN2021/087669 WO2022134395A1 (en) | 2020-12-21 | 2021-04-16 | Novel bh3 mimetic peptide analog inhibiting ptp1b activity and application thereof |
| ZA2022/03821A ZA202203821B (en) | 2020-12-21 | 2022-04-04 | New bh3 mimetic peptide analogue for inhibiting ptp1b activity and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011518318.0A CN112608375B (en) | 2020-12-21 | 2020-12-21 | Novel BH3 mimetic peptide analogue for inhibiting PTP1B activity and application thereof |
Related Child Applications (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210966082.XA Division CN115403664A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof |
| CN202210965783.1A Division CN115403662A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-Q3A and application thereof |
| CN202210965781.2A Division CN115417922A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-F12A and application thereof |
| CN202210965785.0A Division CN115403663A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-I8A and application thereof |
| CN202210965782.7A Division CN115403661A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-G9A and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112608375A true CN112608375A (en) | 2021-04-06 |
| CN112608375B CN112608375B (en) | 2022-10-04 |
Family
ID=75243738
Family Applications (6)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011518318.0A Active CN112608375B (en) | 2020-12-21 | 2020-12-21 | Novel BH3 mimetic peptide analogue for inhibiting PTP1B activity and application thereof |
| CN202210965781.2A Pending CN115417922A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-F12A and application thereof |
| CN202210965785.0A Pending CN115403663A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-I8A and application thereof |
| CN202210965783.1A Pending CN115403662A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-Q3A and application thereof |
| CN202210966082.XA Pending CN115403664A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof |
| CN202210965782.7A Pending CN115403661A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-G9A and application thereof |
Family Applications After (5)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210965781.2A Pending CN115417922A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-F12A and application thereof |
| CN202210965785.0A Pending CN115403663A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-I8A and application thereof |
| CN202210965783.1A Pending CN115403662A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-Q3A and application thereof |
| CN202210966082.XA Pending CN115403664A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-R7A and application thereof |
| CN202210965782.7A Pending CN115403661A (en) | 2020-12-21 | 2020-12-21 | PTP1B polypeptide inhibitor BimBH3-12-G9A and application thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (6) | CN112608375B (en) |
| WO (1) | WO2022134395A1 (en) |
| ZA (1) | ZA202203821B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022134395A1 (en) * | 2020-12-21 | 2022-06-30 | 青岛科技大学 | Novel bh3 mimetic peptide analog inhibiting ptp1b activity and application thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116239652B (en) * | 2022-12-07 | 2023-10-10 | 中国农业大学 | Three oligopeptides derived from red bean and application thereof in controlling obesity and diabetes |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109575108A (en) * | 2018-12-12 | 2019-04-05 | 中国海洋大学 | Using PTP1B as novel B H3 peptide mimics of target spot and its preparation method and application |
| CN109912688A (en) * | 2017-12-12 | 2019-06-21 | 青岛海洋生物医药研究院股份有限公司 | A kind of PTP1B peptide inhibitor and its preparation method and application |
| CN110183515A (en) * | 2019-04-28 | 2019-08-30 | 浙江中医药大学 | It is a kind of for PTP1B detection polypeptide and include the fluorescence probe of the polypeptide |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1781689A4 (en) * | 2004-06-24 | 2010-11-10 | Inst Medical W & E Hall | Conjugates and therapeutic uses thereof |
| CN106565835A (en) * | 2016-11-10 | 2017-04-19 | 青岛海洋生物医药研究院股份有限公司 | Novel BH3 analogue targeted to Bcl-2 family anti-apoptotic protein and application of novel BH3 analogue |
| CN112608375B (en) * | 2020-12-21 | 2022-10-04 | 青岛科技大学 | Novel BH3 mimetic peptide analogue for inhibiting PTP1B activity and application thereof |
-
2020
- 2020-12-21 CN CN202011518318.0A patent/CN112608375B/en active Active
- 2020-12-21 CN CN202210965781.2A patent/CN115417922A/en active Pending
- 2020-12-21 CN CN202210965785.0A patent/CN115403663A/en active Pending
- 2020-12-21 CN CN202210965783.1A patent/CN115403662A/en active Pending
- 2020-12-21 CN CN202210966082.XA patent/CN115403664A/en active Pending
- 2020-12-21 CN CN202210965782.7A patent/CN115403661A/en active Pending
-
2021
- 2021-04-16 WO PCT/CN2021/087669 patent/WO2022134395A1/en active Application Filing
-
2022
- 2022-04-04 ZA ZA2022/03821A patent/ZA202203821B/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109912688A (en) * | 2017-12-12 | 2019-06-21 | 青岛海洋生物医药研究院股份有限公司 | A kind of PTP1B peptide inhibitor and its preparation method and application |
| CN109575108A (en) * | 2018-12-12 | 2019-04-05 | 中国海洋大学 | Using PTP1B as novel B H3 peptide mimics of target spot and its preparation method and application |
| CN110183515A (en) * | 2019-04-28 | 2019-08-30 | 浙江中医药大学 | It is a kind of for PTP1B detection polypeptide and include the fluorescence probe of the polypeptide |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022134395A1 (en) * | 2020-12-21 | 2022-06-30 | 青岛科技大学 | Novel bh3 mimetic peptide analog inhibiting ptp1b activity and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2022134395A9 (en) | 2022-11-24 |
| WO2022134395A1 (en) | 2022-06-30 |
| CN112608375B (en) | 2022-10-04 |
| CN115403663A (en) | 2022-11-29 |
| CN115403662A (en) | 2022-11-29 |
| CN115417922A (en) | 2022-12-02 |
| ZA202203821B (en) | 2022-11-30 |
| CN115403664A (en) | 2022-11-29 |
| CN115403661A (en) | 2022-11-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5364851A (en) | Conformationally restricted biologically active peptides, methods for their production and uses thereof | |
| EP2694095B1 (en) | Compositions comprising glucagon analogs and methods of making and using the same | |
| US9695224B2 (en) | Stabilized insulinotropic peptides and methods of use | |
| CN111253475B (en) | GLP-1 agonist polypeptide compound and salt thereof, and synthesis method and application thereof | |
| US20050037430A1 (en) | Methods and uses for protein breakdown products | |
| CN112608375B (en) | Novel BH3 mimetic peptide analogue for inhibiting PTP1B activity and application thereof | |
| US20090227505A1 (en) | Methods and uses for protein breakdown products | |
| EP3321279B1 (en) | Exenatide modifier and use thereof | |
| CN116712530B (en) | Long-acting GLP-1/glucon/GIP receptor triple agonist and application thereof | |
| CN113929761B (en) | Novel somatostatin analogue peptide reconstruction and dimerization preparation and application thereof | |
| JP2018531217A6 (en) | Exenatide modified products and uses thereof | |
| KR20180043428A (en) | Peptides having Anti-obesity and Anti-Diabetes Effects and Use Thereof | |
| CN109912688B (en) | PTP1B polypeptide inhibitors and preparation method and application thereof | |
| CN114437177B (en) | PUMABH3 mimic peptide compound taking PTP1B as target point, and preparation method and application thereof | |
| WO2015149627A1 (en) | Structurally modified glp-1 analogue and preparation method therefor | |
| LU500160B1 (en) | Novel BH3 Mimetic Peptide Compounds Targeting PTP1B, Preparation Method and Application Thereof | |
| CN117343145A (en) | Long-acting hypoglycemic BimBH3 mimic peptide targeting PTP1B and preparation method and application thereof | |
| US20220143150A1 (en) | Glucagon-like peptide-1 (glp-1) agonist analog, process of preparation and uses thereof | |
| CN117624291A (en) | Uric acid-reducing tetrapeptide with hypoxanthine binding capacity, and encoding gene and application thereof | |
| CN117624333A (en) | GLP-1 receptor, glucagon receptor and GIP receptor tri-excitation polypeptide compound and application thereof | |
| CN115141267A (en) | Polypeptide for improving gastric cancer cisplatin chemotherapy sensitivity and application thereof | |
| CN115960258A (en) | GLP-1/glucagon/Y 2 Receptor triple agonists and uses thereof | |
| CN116789744A (en) | Stapling peptide analogue of opioid/neuropeptide FF receptor multi-target molecule DN-9, preparation and application thereof | |
| CN115536729A (en) | Dipeptide with uric acid reducing activity and encoding gene and application thereof | |
| CN117417431A (en) | Polypeptides with agonistic activity on GLP-1, glucagon and GIP receptor and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |