CA2841933A1 - Alteration of proteolytic cleavage of botulinum neurotoxins - Google Patents
Alteration of proteolytic cleavage of botulinum neurotoxins Download PDFInfo
- Publication number
- CA2841933A1 CA2841933A1 CA2841933A CA2841933A CA2841933A1 CA 2841933 A1 CA2841933 A1 CA 2841933A1 CA 2841933 A CA2841933 A CA 2841933A CA 2841933 A CA2841933 A CA 2841933A CA 2841933 A1 CA2841933 A1 CA 2841933A1
- Authority
- CA
- Canada
- Prior art keywords
- light chain
- dystonia
- bont
- polynucleotide
- calpain
- 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.)
- Abandoned
Links
- 108030001720 Bontoxilysin Proteins 0.000 title description 16
- 231100001103 botulinum neurotoxin Toxicity 0.000 title description 9
- 230000006337 proteolytic cleavage Effects 0.000 title description 4
- 230000004075 alteration Effects 0.000 title description 2
- 239000002581 neurotoxin Substances 0.000 claims abstract description 166
- 231100000618 neurotoxin Toxicity 0.000 claims abstract description 165
- 101710138657 Neurotoxin Proteins 0.000 claims abstract description 152
- 238000003776 cleavage reaction Methods 0.000 claims abstract description 111
- 230000007017 scission Effects 0.000 claims abstract description 111
- 108010032088 Calpain Proteins 0.000 claims abstract description 94
- 102000007590 Calpain Human genes 0.000 claims abstract description 94
- 108091033319 polynucleotide Proteins 0.000 claims abstract description 64
- 239000002157 polynucleotide Substances 0.000 claims abstract description 64
- 102000040430 polynucleotide Human genes 0.000 claims abstract description 64
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 58
- 229920001184 polypeptide Polymers 0.000 claims abstract description 57
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 57
- 230000004048 modification Effects 0.000 claims abstract description 55
- 238000012986 modification Methods 0.000 claims abstract description 55
- 239000000203 mixture Substances 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 28
- 239000013598 vector Substances 0.000 claims abstract description 27
- 101710117542 Botulinum neurotoxin type A Proteins 0.000 claims description 51
- 230000004071 biological effect Effects 0.000 claims description 44
- 208000014094 Dystonic disease Diseases 0.000 claims description 40
- 208000010118 dystonia Diseases 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 20
- 238000006467 substitution reaction Methods 0.000 claims description 18
- 230000001965 increasing effect Effects 0.000 claims description 16
- 101000985023 Clostridium botulinum C phage Botulinum neurotoxin type C Proteins 0.000 claims description 14
- 208000004350 Strabismus Diseases 0.000 claims description 14
- 230000003247 decreasing effect Effects 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 101710117524 Botulinum neurotoxin type B Proteins 0.000 claims description 12
- 206010044074 Torticollis Diseases 0.000 claims description 10
- 238000001356 surgical procedure Methods 0.000 claims description 10
- 239000002537 cosmetic Substances 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 9
- 101710117520 Botulinum neurotoxin type F Proteins 0.000 claims description 8
- 101000933563 Clostridium botulinum Botulinum neurotoxin type G Proteins 0.000 claims description 8
- 101000985020 Clostridium botulinum D phage Botulinum neurotoxin type D Proteins 0.000 claims description 8
- 230000002035 prolonged effect Effects 0.000 claims description 7
- 208000007101 Muscle Cramp Diseases 0.000 claims description 6
- 208000002033 Myoclonus Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 206010067672 Spasmodic dysphonia Diseases 0.000 claims description 6
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 210000003127 knee Anatomy 0.000 claims description 6
- 230000003902 lesion Effects 0.000 claims description 6
- 201000002849 spasmodic dystonia Diseases 0.000 claims description 6
- 210000005070 sphincter Anatomy 0.000 claims description 6
- 206010005159 blepharospasm Diseases 0.000 claims description 5
- 230000000744 blepharospasm Effects 0.000 claims description 5
- 208000012661 Dyskinesia Diseases 0.000 claims description 4
- 206010063006 Facial spasm Diseases 0.000 claims description 4
- 208000004095 Hemifacial Spasm Diseases 0.000 claims description 4
- 208000008454 Hyperhidrosis Diseases 0.000 claims description 4
- 206010020880 Hypertrophy Diseases 0.000 claims description 4
- 206010061216 Infarction Diseases 0.000 claims description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims description 4
- 208000005392 Spasm Diseases 0.000 claims description 4
- 201000003426 X-linked dystonia-parkinsonism Diseases 0.000 claims description 4
- 210000003423 ankle Anatomy 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 210000002683 foot Anatomy 0.000 claims description 4
- 230000037315 hyperhidrosis Effects 0.000 claims description 4
- 206010020718 hyperplasia Diseases 0.000 claims description 4
- 230000007574 infarction Effects 0.000 claims description 4
- 201000002851 oromandibular dystonia Diseases 0.000 claims description 4
- 210000002307 prostate Anatomy 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 210000002027 skeletal muscle Anatomy 0.000 claims description 4
- 210000000689 upper leg Anatomy 0.000 claims description 4
- 206010043376 Tetanus Diseases 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 201000002904 focal dystonia Diseases 0.000 claims description 3
- 210000003205 muscle Anatomy 0.000 claims description 3
- 208000002874 Acne Vulgaris Diseases 0.000 claims description 2
- 206010002153 Anal fissure Diseases 0.000 claims description 2
- 208000016583 Anus disease Diseases 0.000 claims description 2
- 206010002945 Aphakia Diseases 0.000 claims description 2
- 206010003062 Apraxia Diseases 0.000 claims description 2
- 102000014461 Ataxins Human genes 0.000 claims description 2
- 108010078286 Ataxins Proteins 0.000 claims description 2
- 206010059237 Auriculotemporal syndrome Diseases 0.000 claims description 2
- 208000035143 Bacterial infection Diseases 0.000 claims description 2
- 206010069632 Bladder dysfunction Diseases 0.000 claims description 2
- 208000019352 Blepharospasm-oromandibular dystonia syndrome Diseases 0.000 claims description 2
- 208000010392 Bone Fractures Diseases 0.000 claims description 2
- 208000006274 Brain Stem Neoplasms Diseases 0.000 claims description 2
- 206010072043 Central nervous system haemorrhage Diseases 0.000 claims description 2
- 206010008025 Cerebellar ataxia Diseases 0.000 claims description 2
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 2
- 206010008748 Chorea Diseases 0.000 claims description 2
- 208000032170 Congenital Abnormalities Diseases 0.000 claims description 2
- 208000011990 Corticobasal Degeneration Diseases 0.000 claims description 2
- 206010065562 Crocodile tears syndrome Diseases 0.000 claims description 2
- 206010061619 Deformity Diseases 0.000 claims description 2
- 206010013952 Dysphonia Diseases 0.000 claims description 2
- 208000000059 Dyspnea Diseases 0.000 claims description 2
- 206010013975 Dyspnoeas Diseases 0.000 claims description 2
- 206010061842 Entropion Diseases 0.000 claims description 2
- 208000000289 Esophageal Achalasia Diseases 0.000 claims description 2
- 208000001692 Esotropia Diseases 0.000 claims description 2
- 201000005538 Exotropia Diseases 0.000 claims description 2
- 206010015995 Eyelid ptosis Diseases 0.000 claims description 2
- 206010068737 Facial asymmetry Diseases 0.000 claims description 2
- 208000009531 Fissure in Ano Diseases 0.000 claims description 2
- 206010017076 Fracture Diseases 0.000 claims description 2
- 201000001678 Frey syndrome Diseases 0.000 claims description 2
- 206010017533 Fungal infection Diseases 0.000 claims description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 2
- 206010056696 Gaze palsy Diseases 0.000 claims description 2
- 201000004311 Gilles de la Tourette syndrome Diseases 0.000 claims description 2
- 206010018691 Granuloma Diseases 0.000 claims description 2
- 208000004041 Gustatory Sweating Diseases 0.000 claims description 2
- 208000032843 Hemorrhage Diseases 0.000 claims description 2
- 208000023105 Huntington disease Diseases 0.000 claims description 2
- 201000005190 Meige syndrome Diseases 0.000 claims description 2
- 208000008238 Muscle Spasticity Diseases 0.000 claims description 2
- 208000021642 Muscular disease Diseases 0.000 claims description 2
- 208000031888 Mycoses Diseases 0.000 claims description 2
- 208000003926 Myelitis Diseases 0.000 claims description 2
- 206010028632 Myokymia Diseases 0.000 claims description 2
- 201000009623 Myopathy Diseases 0.000 claims description 2
- 208000001738 Nervous System Trauma Diseases 0.000 claims description 2
- 208000008589 Obesity Diseases 0.000 claims description 2
- 206010030136 Oesophageal achalasia Diseases 0.000 claims description 2
- 206010052087 Oscillopsia Diseases 0.000 claims description 2
- 208000030852 Parasitic disease Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 208000012075 Paroxysmal dystonia Diseases 0.000 claims description 2
- 206010035628 Pleurothotonus Diseases 0.000 claims description 2
- 206010036346 Posterior capsule opacification Diseases 0.000 claims description 2
- 206010038848 Retinal detachment Diseases 0.000 claims description 2
- 208000036071 Rhinorrhea Diseases 0.000 claims description 2
- 206010039101 Rhinorrhoea Diseases 0.000 claims description 2
- 206010039424 Salivary hypersecretion Diseases 0.000 claims description 2
- 208000008630 Sialorrhea Diseases 0.000 claims description 2
- 206010048992 Spinal cord haemorrhage Diseases 0.000 claims description 2
- 208000009415 Spinocerebellar Ataxias Diseases 0.000 claims description 2
- 206010072148 Stiff-Person syndrome Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 208000003028 Stuttering Diseases 0.000 claims description 2
- 208000002667 Subdural Hematoma Diseases 0.000 claims description 2
- 206010042364 Subdural haemorrhage Diseases 0.000 claims description 2
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 2
- 208000016620 Tourette disease Diseases 0.000 claims description 2
- 206010044565 Tremor Diseases 0.000 claims description 2
- 208000036142 Viral infection Diseases 0.000 claims description 2
- 208000005248 Vocal Cord Paralysis Diseases 0.000 claims description 2
- 208000013142 Writer cramp Diseases 0.000 claims description 2
- 210000001015 abdomen Anatomy 0.000 claims description 2
- 201000000621 achalasia Diseases 0.000 claims description 2
- 206010000496 acne Diseases 0.000 claims description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 2
- 238000011882 arthroplasty Methods 0.000 claims description 2
- 230000001363 autoimmune Effects 0.000 claims description 2
- 201000004562 autosomal dominant cerebellar ataxia Diseases 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 208000032257 benign familial neonatal 1 seizures Diseases 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 210000000133 brain stem Anatomy 0.000 claims description 2
- 201000007293 brain stem infarction Diseases 0.000 claims description 2
- 206010006514 bruxism Diseases 0.000 claims description 2
- 210000003169 central nervous system Anatomy 0.000 claims description 2
- 206010008129 cerebral palsy Diseases 0.000 claims description 2
- 201000002866 cervical dystonia Diseases 0.000 claims description 2
- 201000011228 clubfoot Diseases 0.000 claims description 2
- 238000012937 correction Methods 0.000 claims description 2
- 239000004053 dental implant Substances 0.000 claims description 2
- 201000003892 detrusor sphincter dyssynergia Diseases 0.000 claims description 2
- 201000011191 dyskinesia of esophagus Diseases 0.000 claims description 2
- 210000000959 ear middle Anatomy 0.000 claims description 2
- 206010014599 encephalitis Diseases 0.000 claims description 2
- 210000003499 exocrine gland Anatomy 0.000 claims description 2
- 201000002865 focal hand dystonia Diseases 0.000 claims description 2
- 208000031477 focal task-specific dystonia Diseases 0.000 claims description 2
- 201000002842 hemidystonia Diseases 0.000 claims description 2
- 208000018295 hereditary geniospasm Diseases 0.000 claims description 2
- 208000008675 hereditary spastic paraplegia Diseases 0.000 claims description 2
- 210000004394 hip joint Anatomy 0.000 claims description 2
- 208000013403 hyperactivity Diseases 0.000 claims description 2
- 230000001969 hypertrophic effect Effects 0.000 claims description 2
- 208000018197 inherited torticollis Diseases 0.000 claims description 2
- 208000020658 intracerebral hemorrhage Diseases 0.000 claims description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
- 210000000867 larynx Anatomy 0.000 claims description 2
- 210000002414 leg Anatomy 0.000 claims description 2
- 201000006417 multiple sclerosis Diseases 0.000 claims description 2
- 230000000869 mutational effect Effects 0.000 claims description 2
- 230000009826 neoplastic cell growth Effects 0.000 claims description 2
- 208000008795 neuromyelitis optica Diseases 0.000 claims description 2
- 206010029864 nystagmus Diseases 0.000 claims description 2
- 231100000898 oscillopsia Toxicity 0.000 claims description 2
- 208000002593 pantothenate kinase-associated neurodegeneration Diseases 0.000 claims description 2
- 230000001769 paralizing effect Effects 0.000 claims description 2
- 230000002980 postoperative effect Effects 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 201000003004 ptosis Diseases 0.000 claims description 2
- 230000007832 reinnervation Effects 0.000 claims description 2
- 230000004264 retinal detachment Effects 0.000 claims description 2
- 201000002899 segmental dystonia Diseases 0.000 claims description 2
- 230000001148 spastic effect Effects 0.000 claims description 2
- 208000018198 spasticity Diseases 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 210000002435 tendon Anatomy 0.000 claims description 2
- 208000009174 transverse myelitis Diseases 0.000 claims description 2
- 206010046947 vaginismus Diseases 0.000 claims description 2
- 230000009385 viral infection Effects 0.000 claims description 2
- 210000001260 vocal cord Anatomy 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 230000037303 wrinkles Effects 0.000 claims description 2
- 230000035772 mutation Effects 0.000 description 52
- 210000004027 cell Anatomy 0.000 description 48
- 108090000623 proteins and genes Proteins 0.000 description 26
- 235000018102 proteins Nutrition 0.000 description 25
- 102000004169 proteins and genes Human genes 0.000 description 25
- 230000002688 persistence Effects 0.000 description 19
- 125000003275 alpha amino acid group Chemical group 0.000 description 18
- 101710117515 Botulinum neurotoxin type E Proteins 0.000 description 16
- 210000002569 neuron Anatomy 0.000 description 15
- 125000000539 amino acid group Chemical group 0.000 description 14
- 238000006731 degradation reaction Methods 0.000 description 14
- 230000015556 catabolic process Effects 0.000 description 12
- 108010055044 Tetanus Toxin Proteins 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 11
- 230000005847 immunogenicity Effects 0.000 description 11
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 10
- 235000004279 alanine Nutrition 0.000 description 10
- 238000003556 assay Methods 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 229960000310 isoleucine Drugs 0.000 description 9
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 230000001105 regulatory effect Effects 0.000 description 9
- 235000001014 amino acid Nutrition 0.000 description 8
- 230000028023 exocytosis Effects 0.000 description 8
- 108010011767 m-calpain Proteins 0.000 description 8
- 102000003895 Calpain-1 Human genes 0.000 description 7
- 108090000236 Calpain-1 Proteins 0.000 description 7
- 102000003900 Calpain-2 Human genes 0.000 description 7
- 108090000232 Calpain-2 Proteins 0.000 description 7
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 108091028043 Nucleic acid sequence Proteins 0.000 description 7
- 229940024606 amino acid Drugs 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- 230000002797 proteolythic effect Effects 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 6
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 6
- 229960004373 acetylcholine Drugs 0.000 description 6
- 230000001580 bacterial effect Effects 0.000 description 6
- 238000012217 deletion Methods 0.000 description 6
- 230000037430 deletion Effects 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 239000013604 expression vector Substances 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 6
- 229940118376 tetanus toxin Drugs 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 5
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 5
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 5
- 102000035195 Peptidases Human genes 0.000 description 5
- 108091005804 Peptidases Proteins 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 239000002858 neurotransmitter agent Substances 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 238000013518 transcription Methods 0.000 description 5
- 230000035897 transcription Effects 0.000 description 5
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 5
- 241000193155 Clostridium botulinum Species 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 239000004365 Protease Substances 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- -1 hnRNA Proteins 0.000 description 4
- 150000007523 nucleic acids Chemical group 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- 230000005945 translocation Effects 0.000 description 4
- 241000193449 Clostridium tetani Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 3
- 206010033799 Paralysis Diseases 0.000 description 3
- 108091006629 SLC13A2 Proteins 0.000 description 3
- 102000000583 SNARE Proteins Human genes 0.000 description 3
- 108010041948 SNARE Proteins Proteins 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 210000004899 c-terminal region Anatomy 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 235000013922 glutamic acid Nutrition 0.000 description 3
- 239000004220 glutamic acid Substances 0.000 description 3
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000017854 proteolysis Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 239000004474 valine Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- 102100035037 Calpastatin Human genes 0.000 description 2
- 241001112695 Clostridiales Species 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 241000238631 Hexapoda Species 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 102000004183 Synaptosomal-Associated Protein 25 Human genes 0.000 description 2
- 108010057722 Synaptosomal-Associated Protein 25 Proteins 0.000 description 2
- 108030001722 Tentoxilysin Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 108010044208 calpastatin Proteins 0.000 description 2
- ZXJCOYBPXOBJMU-HSQGJUDPSA-N calpastatin peptide Ac 184-210 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCSC)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(O)=O)NC(C)=O)[C@@H](C)O)C1=CC=C(O)C=C1 ZXJCOYBPXOBJMU-HSQGJUDPSA-N 0.000 description 2
- 230000006800 cellular catabolic process Effects 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 210000000172 cytosol Anatomy 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 230000006806 disease prevention Effects 0.000 description 2
- 230000003241 endoproteolytic effect Effects 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 238000002703 mutagenesis Methods 0.000 description 2
- 231100000350 mutagenesis Toxicity 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 239000013600 plasmid vector Substances 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 229940124272 protein stabilizer Drugs 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- FGDZQCVHDSGLHJ-UHFFFAOYSA-M rubidium chloride Chemical compound [Cl-].[Rb+] FGDZQCVHDSGLHJ-UHFFFAOYSA-M 0.000 description 2
- 238000002864 sequence alignment Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 238000001542 size-exclusion chromatography Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000194107 Bacillus megaterium Species 0.000 description 1
- 208000003508 Botulism Diseases 0.000 description 1
- 241000701822 Bovine papillomavirus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102100029398 Calpain small subunit 1 Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 101710101803 DNA-binding protein J Proteins 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000005593 Endopeptidases Human genes 0.000 description 1
- 108010059378 Endopeptidases Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- 101000919194 Homo sapiens Calpain small subunit 1 Proteins 0.000 description 1
- 101000582320 Homo sapiens Neurogenic differentiation factor 6 Proteins 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 241000579835 Merops Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- 102100030589 Neurogenic differentiation factor 6 Human genes 0.000 description 1
- 101710182846 Polyhedrin Proteins 0.000 description 1
- 101710118538 Protease Proteins 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 241000714474 Rous sarcoma virus Species 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000012505 Superdex™ Substances 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001153 anti-wrinkle effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000004436 artificial bacterial chromosome Anatomy 0.000 description 1
- 210000001106 artificial yeast chromosome Anatomy 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000005277 cation exchange chromatography Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000004590 computer program Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000004520 electroporation Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 229940066758 endopeptidases Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 102000018146 globin Human genes 0.000 description 1
- 108060003196 globin Proteins 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000034217 membrane fusion Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 230000003387 muscular Effects 0.000 description 1
- 230000025743 negative regulation of exocytosis Effects 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 230000003957 neurotransmitter release Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 229940024999 proteolytic enzymes for treatment of wounds and ulcers Drugs 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940102127 rubidium chloride Drugs 0.000 description 1
- 238000007665 sagging Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004960 subcellular localization Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 210000002504 synaptic vesicle Anatomy 0.000 description 1
- 230000021966 synaptic vesicle transport Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase
- A61K38/4893—Botulinum neurotoxin (3.4.24.69)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- 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
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- 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
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/33—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Clostridium (G)
-
- 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
-
- 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
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/52—Genes encoding for enzymes or proenzymes
-
- 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)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/24—Metalloendopeptidases (3.4.24)
- C12Y304/24069—Bontoxilysin (3.4.24.69), i.e. botulinum neurotoxin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Zoology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Biochemistry (AREA)
- Wood Science & Technology (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Engineering & Computer Science (AREA)
- Neurology (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Neurosurgery (AREA)
- Biotechnology (AREA)
- Toxicology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Microbiology (AREA)
- Pain & Pain Management (AREA)
- Psychology (AREA)
- Plant Pathology (AREA)
- Physics & Mathematics (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Diabetes (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161574596P | 2011-08-04 | 2011-08-04 | |
| EP11176531.9 | 2011-08-04 | ||
| EP11176531 | 2011-08-04 | ||
| US61/574,596 | 2011-08-04 | ||
| PCT/EP2012/064690 WO2013017522A1 (en) | 2011-08-04 | 2012-07-26 | Alteration of proteolytic cleavage of botulinum neurotoxins |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2841933A1 true CA2841933A1 (en) | 2013-02-07 |
Family
ID=47628649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2841933A Abandoned CA2841933A1 (en) | 2011-08-04 | 2012-07-26 | Alteration of proteolytic cleavage of botulinum neurotoxins |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US20140170133A1 (enExample) |
| EP (1) | EP2739297A1 (enExample) |
| JP (1) | JP2014529395A (enExample) |
| AU (1) | AU2012292163A1 (enExample) |
| CA (1) | CA2841933A1 (enExample) |
| WO (1) | WO2013017522A1 (enExample) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3290437A1 (en) | 2016-08-31 | 2018-03-07 | Merz Pharma GmbH & Co. KGaA | Novel recombinant clostridial neurotoxins with decreased duration of effect |
| EP3312193A1 (en) | 2016-10-19 | 2018-04-25 | Merz Pharma GmbH & Co. KGaA | Novel recombinant botulinum neurotoxins with accelerated onset of effect |
| WO2018081282A1 (en) * | 2016-10-25 | 2018-05-03 | Cellsnap Llc | Neurotoxins and uses thereof |
| EP3335719A1 (en) * | 2016-12-14 | 2018-06-20 | Merz Pharma GmbH & Co. KGaA | Novel recombinant botulinum neurotoxins with a stabilized light chain |
| CN118126143B (zh) * | 2024-03-14 | 2025-06-24 | 河北平朴生物科技合伙企业(有限合伙) | 一种a型肉毒毒素的突变体及其应用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5939070A (en) * | 1996-10-28 | 1999-08-17 | Wisconsin Alumni Research Foundation | Hybrid botulinal neurotoxins |
| US6903187B1 (en) * | 2000-07-21 | 2005-06-07 | Allergan, Inc. | Leucine-based motif and clostridial neurotoxins |
| US20030219462A1 (en) * | 2000-07-21 | 2003-11-27 | Allergan Sales, Inc | Clostridial neurotoxin compositions and modified clostridial neurotoxins |
| US6943555B2 (en) * | 2002-05-23 | 2005-09-13 | Lockheed Martin Corporation | Redundant safety circuit for squib testing |
| ES2592314T3 (es) * | 2008-08-29 | 2016-11-29 | Merz Pharma Gmbh & Co. Kgaa | Neurotoxinas clostridiales con persistencia modificada |
| GB0903006D0 (en) * | 2009-02-23 | 2009-04-08 | Syntaxin Ltd | Modified non-cytotoxic proteases |
-
2012
- 2012-07-26 WO PCT/EP2012/064690 patent/WO2013017522A1/en not_active Ceased
- 2012-07-26 AU AU2012292163A patent/AU2012292163A1/en not_active Abandoned
- 2012-07-26 CA CA2841933A patent/CA2841933A1/en not_active Abandoned
- 2012-07-26 US US14/236,454 patent/US20140170133A1/en not_active Abandoned
- 2012-07-26 EP EP12742873.8A patent/EP2739297A1/en not_active Withdrawn
- 2012-07-26 JP JP2014523291A patent/JP2014529395A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| US20140170133A1 (en) | 2014-06-19 |
| JP2014529395A (ja) | 2014-11-13 |
| WO2013017522A1 (en) | 2013-02-07 |
| EP2739297A1 (en) | 2014-06-11 |
| AU2012292163A1 (en) | 2014-02-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11441141B2 (en) | Methods for the manufacture of proteolytically processed polypeptides | |
| RU2582266C2 (ru) | Нейротоксины, проявляющие сокращенную биологическую активность | |
| US9314514B2 (en) | Modified neurotoxins with poly-glycine and uses thereof | |
| EP3162894B1 (en) | Methods for the manufacture of proteolytically processed polypeptides | |
| UA129511C2 (uk) | СПОСІБ ОДЕРЖАННЯ РОЗЧИННОГО ДВОЛАНЦЮГОВОГО BoNT/A БІЛКА | |
| AU2012292163A1 (en) | Alteration of proteolytic cleavage of botulinum neurotoxins | |
| WO2012041761A2 (en) | Botulinum neurotoxin polypeptides exhibiting a prolonged activity | |
| EP3290437A1 (en) | Novel recombinant clostridial neurotoxins with decreased duration of effect | |
| HK1236999B (en) | Methods for the manufacture of proteolytically processed polypeptides | |
| HK1236999A (en) | Methods for the manufacture of proteolytically processed polypeptides | |
| HK1236999A1 (en) | Methods for the manufacture of proteolytically processed polypeptides | |
| HK1187643B (en) | Methods for the manufacture of proteolytically processed polypeptides | |
| HK1187643A (en) | Methods for the manufacture of proteolytically processed polypeptides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
Effective date: 20180726 |