WO2002051233A2 - Universal antimicrobial treatment - Google Patents
Universal antimicrobial treatment Download PDFInfo
- Publication number
- WO2002051233A2 WO2002051233A2 PCT/EP2002/002302 EP0202302W WO02051233A2 WO 2002051233 A2 WO2002051233 A2 WO 2002051233A2 EP 0202302 W EP0202302 W EP 0202302W WO 02051233 A2 WO02051233 A2 WO 02051233A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- proteins
- hiv
- antibodies
- contamination
- protein
- Prior art date
Links
- 230000000845 anti-microbial effect Effects 0.000 title description 3
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 268
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 258
- 238000011109 contamination Methods 0.000 claims abstract description 193
- 241000700605 Viruses Species 0.000 claims abstract description 145
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 95
- 210000002540 macrophage Anatomy 0.000 claims abstract description 89
- 239000002245 particle Substances 0.000 claims abstract description 63
- 238000010494 dissociation reaction Methods 0.000 claims abstract description 54
- 230000005593 dissociations Effects 0.000 claims abstract description 54
- 102000004196 processed proteins & peptides Human genes 0.000 claims abstract description 46
- 102000009658 Peptidylprolyl Isomerase Human genes 0.000 claims abstract description 30
- 108010020062 Peptidylprolyl Isomerase Proteins 0.000 claims abstract description 30
- 230000002776 aggregation Effects 0.000 claims abstract description 27
- 238000004220 aggregation Methods 0.000 claims abstract description 25
- 230000014616 translation Effects 0.000 claims abstract description 25
- 230000034994 death Effects 0.000 claims abstract description 22
- 231100000517 death Toxicity 0.000 claims abstract description 22
- 230000011664 signaling Effects 0.000 claims abstract description 20
- 238000001243 protein synthesis Methods 0.000 claims abstract description 18
- 230000007704 transition Effects 0.000 claims abstract description 18
- 208000030507 AIDS Diseases 0.000 claims abstract description 14
- 230000000147 hypnotic effect Effects 0.000 claims abstract description 7
- 239000003326 hypnotic agent Substances 0.000 claims abstract description 6
- 206010010071 Coma Diseases 0.000 claims abstract description 5
- 102000002278 Ribosomal Proteins Human genes 0.000 claims abstract description 5
- 108010000605 Ribosomal Proteins Proteins 0.000 claims abstract description 5
- 230000003472 neutralizing effect Effects 0.000 claims abstract description 5
- 235000018102 proteins Nutrition 0.000 claims description 253
- 210000004027 cell Anatomy 0.000 claims description 241
- 230000003993 interaction Effects 0.000 claims description 164
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 147
- 150000001720 carbohydrates Chemical class 0.000 claims description 116
- 108090000624 Cathepsin L Proteins 0.000 claims description 82
- 102000004172 Cathepsin L Human genes 0.000 claims description 81
- 235000014633 carbohydrates Nutrition 0.000 claims description 74
- 230000017854 proteolysis Effects 0.000 claims description 71
- 230000003612 virological effect Effects 0.000 claims description 71
- 210000000805 cytoplasm Anatomy 0.000 claims description 70
- 102000005962 receptors Human genes 0.000 claims description 70
- 108020003175 receptors Proteins 0.000 claims description 70
- 210000003705 ribosome Anatomy 0.000 claims description 68
- 230000015572 biosynthetic process Effects 0.000 claims description 62
- 230000007246 mechanism Effects 0.000 claims description 58
- 230000004913 activation Effects 0.000 claims description 57
- 210000004940 nucleus Anatomy 0.000 claims description 56
- 210000000170 cell membrane Anatomy 0.000 claims description 52
- 238000001727 in vivo Methods 0.000 claims description 51
- 238000011161 development Methods 0.000 claims description 50
- 230000018109 developmental process Effects 0.000 claims description 50
- 238000003786 synthesis reaction Methods 0.000 claims description 49
- 230000009471 action Effects 0.000 claims description 46
- 230000000694 effects Effects 0.000 claims description 46
- 108010087819 Fc receptors Proteins 0.000 claims description 43
- 102000009109 Fc receptors Human genes 0.000 claims description 43
- 238000000338 in vitro Methods 0.000 claims description 40
- 108020004999 messenger RNA Proteins 0.000 claims description 40
- 230000001965 increasing effect Effects 0.000 claims description 39
- 108020003519 protein disulfide isomerase Proteins 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 37
- 102000006010 Protein Disulfide-Isomerase Human genes 0.000 claims description 34
- 230000001086 cytosolic effect Effects 0.000 claims description 34
- 208000015181 infectious disease Diseases 0.000 claims description 32
- 230000008569 process Effects 0.000 claims description 32
- 238000004519 manufacturing process Methods 0.000 claims description 30
- HLXHCNWEVQNNKA-UHFFFAOYSA-N 5-methoxy-2,3-dihydro-1h-inden-2-amine Chemical compound COC1=CC=C2CC(N)CC2=C1 HLXHCNWEVQNNKA-UHFFFAOYSA-N 0.000 claims description 27
- 108020004414 DNA Proteins 0.000 claims description 27
- 239000000427 antigen Substances 0.000 claims description 27
- 108091007433 antigens Proteins 0.000 claims description 27
- 102000036639 antigens Human genes 0.000 claims description 27
- 230000032258 transport Effects 0.000 claims description 27
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 26
- 238000006206 glycosylation reaction Methods 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 25
- 230000013595 glycosylation Effects 0.000 claims description 25
- 235000013930 proline Nutrition 0.000 claims description 24
- 108010067390 Viral Proteins Proteins 0.000 claims description 23
- 230000008859 change Effects 0.000 claims description 23
- 108010078428 env Gene Products Proteins 0.000 claims description 23
- 238000002255 vaccination Methods 0.000 claims description 23
- 208000031886 HIV Infections Diseases 0.000 claims description 22
- 230000012202 endocytosis Effects 0.000 claims description 22
- 230000012846 protein folding Effects 0.000 claims description 22
- 102000004190 Enzymes Human genes 0.000 claims description 21
- 108090000790 Enzymes Proteins 0.000 claims description 21
- 102100034353 Integrase Human genes 0.000 claims description 21
- 150000001413 amino acids Chemical class 0.000 claims description 21
- 230000033001 locomotion Effects 0.000 claims description 21
- 210000001616 monocyte Anatomy 0.000 claims description 21
- 235000001014 amino acid Nutrition 0.000 claims description 20
- 230000001413 cellular effect Effects 0.000 claims description 20
- 210000003719 b-lymphocyte Anatomy 0.000 claims description 19
- 230000009087 cell motility Effects 0.000 claims description 19
- 102100021010 Nucleolin Human genes 0.000 claims description 18
- 108010044762 nucleolin Proteins 0.000 claims description 18
- 210000003956 transport vesicle Anatomy 0.000 claims description 18
- 102100034349 Integrase Human genes 0.000 claims description 17
- 230000007423 decrease Effects 0.000 claims description 17
- 150000003148 prolines Chemical class 0.000 claims description 17
- 230000000840 anti-viral effect Effects 0.000 claims description 16
- 210000004369 blood Anatomy 0.000 claims description 16
- 239000008280 blood Substances 0.000 claims description 16
- 244000045947 parasite Species 0.000 claims description 16
- 230000037361 pathway Effects 0.000 claims description 16
- 108010041397 CD4 Antigens Proteins 0.000 claims description 15
- 102100021868 Calnexin Human genes 0.000 claims description 13
- 108010056891 Calnexin Proteins 0.000 claims description 13
- 102000004127 Cytokines Human genes 0.000 claims description 13
- 108090000695 Cytokines Proteins 0.000 claims description 13
- 241000282577 Pan troglodytes Species 0.000 claims description 13
- 230000006907 apoptotic process Effects 0.000 claims description 13
- 230000008030 elimination Effects 0.000 claims description 13
- 238000003379 elimination reaction Methods 0.000 claims description 13
- 241000894006 Bacteria Species 0.000 claims description 12
- 108090000549 Calreticulin Proteins 0.000 claims description 12
- 102000004082 Calreticulin Human genes 0.000 claims description 12
- 230000016784 immunoglobulin production Effects 0.000 claims description 12
- 210000000056 organ Anatomy 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- 230000028327 secretion Effects 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- 101100016370 Danio rerio hsp90a.1 gene Proteins 0.000 claims description 11
- 101100285708 Dictyostelium discoideum hspD gene Proteins 0.000 claims description 11
- 108091054437 MHC class I family Proteins 0.000 claims description 11
- 108091005804 Peptidases Proteins 0.000 claims description 11
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 claims description 11
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 claims description 11
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 claims description 11
- 101100071627 Schizosaccharomyces pombe (strain 972 / ATCC 24843) swo1 gene Proteins 0.000 claims description 11
- 108010085012 Steroid Receptors Proteins 0.000 claims description 11
- 102000019034 Chemokines Human genes 0.000 claims description 10
- 108010012236 Chemokines Proteins 0.000 claims description 10
- 102000003886 Glycoproteins Human genes 0.000 claims description 10
- 108090000288 Glycoproteins Proteins 0.000 claims description 10
- 241000713340 Human immunodeficiency virus 2 Species 0.000 claims description 10
- 102100036011 T-cell surface glycoprotein CD4 Human genes 0.000 claims description 10
- 210000004556 brain Anatomy 0.000 claims description 10
- 210000000987 immune system Anatomy 0.000 claims description 10
- 230000004807 localization Effects 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 230000003213 activating effect Effects 0.000 claims description 9
- 230000024203 complement activation Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 230000005764 inhibitory process Effects 0.000 claims description 9
- 230000008018 melting Effects 0.000 claims description 9
- 238000002844 melting Methods 0.000 claims description 9
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 9
- 230000028973 vesicle-mediated transport Effects 0.000 claims description 9
- 101710091045 Envelope protein Proteins 0.000 claims description 8
- 101710188315 Protein X Proteins 0.000 claims description 8
- 230000000295 complement effect Effects 0.000 claims description 8
- 102000005525 fibrillarin Human genes 0.000 claims description 8
- 108020002231 fibrillarin Proteins 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 238000002649 immunization Methods 0.000 claims description 8
- 210000003632 microfilament Anatomy 0.000 claims description 8
- 230000004899 motility Effects 0.000 claims description 8
- 210000002569 neuron Anatomy 0.000 claims description 8
- 229920001184 polypeptide Polymers 0.000 claims description 8
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims description 7
- 102000001902 CC Chemokines Human genes 0.000 claims description 7
- 108010040471 CC Chemokines Proteins 0.000 claims description 7
- 108091008927 CC chemokine receptors Proteins 0.000 claims description 7
- 102000018679 Tacrolimus Binding Proteins Human genes 0.000 claims description 7
- 108010027179 Tacrolimus Binding Proteins Proteins 0.000 claims description 7
- 239000005556 hormone Substances 0.000 claims description 7
- 229940088597 hormone Drugs 0.000 claims description 7
- 230000035515 penetration Effects 0.000 claims description 7
- 102000043129 MHC class I family Human genes 0.000 claims description 6
- 102000007999 Nuclear Proteins Human genes 0.000 claims description 6
- 108010089610 Nuclear Proteins Proteins 0.000 claims description 6
- 108010003533 Viral Envelope Proteins Proteins 0.000 claims description 6
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 6
- 230000036039 immunity Effects 0.000 claims description 6
- 229920002521 macromolecule Polymers 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 102000018071 Immunoglobulin Fc Fragments Human genes 0.000 claims description 5
- 108010091135 Immunoglobulin Fc Fragments Proteins 0.000 claims description 5
- 101100400378 Mus musculus Marveld2 gene Proteins 0.000 claims description 5
- 230000002255 enzymatic effect Effects 0.000 claims description 5
- 230000008570 general process Effects 0.000 claims description 5
- 235000001727 glucose Nutrition 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 230000010354 integration Effects 0.000 claims description 5
- 230000009878 intermolecular interaction Effects 0.000 claims description 5
- 230000002427 irreversible effect Effects 0.000 claims description 5
- 230000036961 partial effect Effects 0.000 claims description 5
- 230000000946 synaptic effect Effects 0.000 claims description 5
- 238000013518 transcription Methods 0.000 claims description 5
- 230000035897 transcription Effects 0.000 claims description 5
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 claims description 4
- 101100507655 Canis lupus familiaris HSPA1 gene Proteins 0.000 claims description 4
- 102000035195 Peptidases Human genes 0.000 claims description 4
- 206010035664 Pneumonia Diseases 0.000 claims description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 4
- 102000019361 Syndecan Human genes 0.000 claims description 4
- 108050006774 Syndecan Proteins 0.000 claims description 4
- 238000013459 approach Methods 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 230000006037 cell lysis Effects 0.000 claims description 4
- 230000000739 chaotic effect Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 102000006834 complement receptors Human genes 0.000 claims description 4
- 108010047295 complement receptors Proteins 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 4
- 238000006297 dehydration reaction Methods 0.000 claims description 4
- 230000003053 immunization Effects 0.000 claims description 4
- 208000037797 influenza A Diseases 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 230000002269 spontaneous effect Effects 0.000 claims description 4
- 108010077544 Chromatin Proteins 0.000 claims description 3
- 101100011744 Dictyostelium discoideum grp94 gene Proteins 0.000 claims description 3
- 101100125027 Dictyostelium discoideum mhsp70 gene Proteins 0.000 claims description 3
- 206010013457 Dissociation Diseases 0.000 claims description 3
- 108010043685 GPI-Linked Proteins Proteins 0.000 claims description 3
- 102000002702 GPI-Linked Proteins Human genes 0.000 claims description 3
- 101150031823 HSP70 gene Proteins 0.000 claims description 3
- 206010057249 Phagocytosis Diseases 0.000 claims description 3
- 102000045595 Phosphoprotein Phosphatases Human genes 0.000 claims description 3
- 108700019535 Phosphoprotein Phosphatases Proteins 0.000 claims description 3
- 230000000903 blocking effect Effects 0.000 claims description 3
- 210000003483 chromatin Anatomy 0.000 claims description 3
- 238000005520 cutting process Methods 0.000 claims description 3
- 125000004122 cyclic group Chemical group 0.000 claims description 3
- 208000018459 dissociative disease Diseases 0.000 claims description 3
- 101150052825 dnaK gene Proteins 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 206010022000 influenza Diseases 0.000 claims description 3
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 3
- 230000007170 pathology Effects 0.000 claims description 3
- 230000008782 phagocytosis Effects 0.000 claims description 3
- 108020004418 ribosomal RNA Proteins 0.000 claims description 3
- 230000007958 sleep Effects 0.000 claims description 3
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims description 2
- 102000002151 Microfilament Proteins Human genes 0.000 claims description 2
- 108010040897 Microfilament Proteins Proteins 0.000 claims description 2
- 208000025747 Rheumatic disease Diseases 0.000 claims description 2
- 230000001133 acceleration Effects 0.000 claims description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000018417 cysteine Nutrition 0.000 claims description 2
- 230000003436 cytoskeletal effect Effects 0.000 claims description 2
- 150000002304 glucoses Chemical class 0.000 claims description 2
- 108091005452 macrophage Fc receptors Proteins 0.000 claims description 2
- 230000001575 pathological effect Effects 0.000 claims description 2
- 230000004481 post-translational protein modification Effects 0.000 claims description 2
- 230000004845 protein aggregation Effects 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 102000005969 steroid hormone receptors Human genes 0.000 claims 3
- 230000008863 intramolecular interaction Effects 0.000 claims 2
- 230000007781 signaling event Effects 0.000 claims 2
- 101100220087 Caenorhabditis elegans cdc-37 gene Proteins 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- 102000012745 Immunoglobulin Subunits Human genes 0.000 claims 1
- 108010079585 Immunoglobulin Subunits Proteins 0.000 claims 1
- 230000000172 allergic effect Effects 0.000 claims 1
- 208000010668 atopic eczema Diseases 0.000 claims 1
- 230000031018 biological processes and functions Effects 0.000 claims 1
- 230000001889 chemoattractive effect Effects 0.000 claims 1
- 235000019833 protease Nutrition 0.000 claims 1
- 210000003370 receptor cell Anatomy 0.000 claims 1
- 125000002345 steroid group Chemical group 0.000 claims 1
- 108020003113 steroid hormone receptors Proteins 0.000 claims 1
- 229960005486 vaccine Drugs 0.000 abstract description 11
- 241001465754 Metazoa Species 0.000 abstract description 7
- 231100000518 lethal Toxicity 0.000 abstract description 3
- 230000001665 lethal effect Effects 0.000 abstract description 3
- 102000003923 Protein Kinase C Human genes 0.000 description 63
- 108090000315 Protein Kinase C Proteins 0.000 description 63
- 238000001994 activation Methods 0.000 description 53
- 210000002472 endoplasmic reticulum Anatomy 0.000 description 52
- 102100037422 Receptor-type tyrosine-protein phosphatase C Human genes 0.000 description 48
- 101000738771 Homo sapiens Receptor-type tyrosine-protein phosphatase C Proteins 0.000 description 47
- 230000000875 corresponding effect Effects 0.000 description 40
- 229940027941 immunoglobulin g Drugs 0.000 description 36
- 230000027455 binding Effects 0.000 description 31
- 108020004705 Codon Proteins 0.000 description 26
- 241000238631 Hexapoda Species 0.000 description 24
- 108700018351 Major Histocompatibility Complex Proteins 0.000 description 23
- 230000020382 suppression by virus of host antigen processing and presentation of peptide antigen via MHC class I Effects 0.000 description 23
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 22
- 238000012790 confirmation Methods 0.000 description 21
- 229960002555 zidovudine Drugs 0.000 description 21
- 230000004989 O-glycosylation Effects 0.000 description 20
- 230000004927 fusion Effects 0.000 description 20
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 18
- 102000003974 Fibroblast growth factor 2 Human genes 0.000 description 18
- 229940024606 amino acid Drugs 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000011575 calcium Substances 0.000 description 17
- 210000004970 cd4 cell Anatomy 0.000 description 17
- 206010028980 Neoplasm Diseases 0.000 description 16
- 241000713311 Simian immunodeficiency virus Species 0.000 description 16
- 230000002085 persistent effect Effects 0.000 description 16
- 102000008122 Casein Kinase I Human genes 0.000 description 15
- 108010049812 Casein Kinase I Proteins 0.000 description 15
- 241001430294 unidentified retrovirus Species 0.000 description 15
- 238000011144 upstream manufacturing Methods 0.000 description 15
- 241000282414 Homo sapiens Species 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 230000036436 anti-hiv Effects 0.000 description 14
- 201000011510 cancer Diseases 0.000 description 14
- 102000007469 Actins Human genes 0.000 description 13
- 108010085238 Actins Proteins 0.000 description 13
- 102000006486 Phosphoinositide Phospholipase C Human genes 0.000 description 13
- 108010044302 Phosphoinositide phospholipase C Proteins 0.000 description 13
- 235000009697 arginine Nutrition 0.000 description 12
- YDGMGEXADBMOMJ-UHFFFAOYSA-N asymmetrical dimethylarginine Natural products CN(C)C(N)=NCCCC(N)C(O)=O YDGMGEXADBMOMJ-UHFFFAOYSA-N 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 230000002458 infectious effect Effects 0.000 description 12
- 210000004698 lymphocyte Anatomy 0.000 description 12
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 11
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 11
- 239000004475 Arginine Substances 0.000 description 11
- 210000004366 CD4-positive T-lymphocyte Anatomy 0.000 description 11
- 241000701022 Cytomegalovirus Species 0.000 description 11
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 11
- 102100039337 NF-kappa-B inhibitor alpha Human genes 0.000 description 11
- 101710083073 NF-kappa-B inhibitor alpha Proteins 0.000 description 11
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 11
- 230000005540 biological transmission Effects 0.000 description 11
- 210000000822 natural killer cell Anatomy 0.000 description 11
- 239000002773 nucleotide Substances 0.000 description 11
- 230000004224 protection Effects 0.000 description 11
- 241000282693 Cercopithecidae Species 0.000 description 10
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 10
- 206010062016 Immunosuppression Diseases 0.000 description 10
- YDGMGEXADBMOMJ-LURJTMIESA-N N(g)-dimethylarginine Chemical compound CN(C)C(\N)=N\CCC[C@H](N)C(O)=O YDGMGEXADBMOMJ-LURJTMIESA-N 0.000 description 10
- 239000004365 Protease Substances 0.000 description 10
- 101710192141 Protein Nef Proteins 0.000 description 10
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 10
- 230000036982 action potential Effects 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 229930004094 glycosylphosphatidylinositol Natural products 0.000 description 10
- 230000001506 immunosuppresive effect Effects 0.000 description 10
- 238000011065 in-situ storage Methods 0.000 description 10
- 239000002523 lectin Substances 0.000 description 10
- 125000003729 nucleotide group Chemical group 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 9
- 108060003951 Immunoglobulin Proteins 0.000 description 9
- 102000004856 Lectins Human genes 0.000 description 9
- 108090001090 Lectins Proteins 0.000 description 9
- 241000282579 Pan Species 0.000 description 9
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 9
- 102000007451 Steroid Receptors Human genes 0.000 description 9
- 102100023132 Transcription factor Jun Human genes 0.000 description 9
- 239000012634 fragment Substances 0.000 description 9
- 102000018358 immunoglobulin Human genes 0.000 description 9
- 206010037844 rash Diseases 0.000 description 9
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 8
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 8
- 108010057466 NF-kappa B Proteins 0.000 description 8
- 102000003945 NF-kappa B Human genes 0.000 description 8
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 8
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 8
- 210000003050 axon Anatomy 0.000 description 8
- 230000003834 intracellular effect Effects 0.000 description 8
- 239000003446 ligand Substances 0.000 description 8
- 210000003205 muscle Anatomy 0.000 description 8
- 150000002482 oligosaccharides Polymers 0.000 description 8
- 150000003905 phosphatidylinositols Chemical class 0.000 description 8
- 241000894007 species Species 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 241000283690 Bos taurus Species 0.000 description 7
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 7
- 102100038132 Endogenous retrovirus group K member 6 Pro protein Human genes 0.000 description 7
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 7
- 102100037850 Interferon gamma Human genes 0.000 description 7
- 108010074328 Interferon-gamma Proteins 0.000 description 7
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 7
- 241000713666 Lentivirus Species 0.000 description 7
- 230000004988 N-glycosylation Effects 0.000 description 7
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 230000008602 contraction Effects 0.000 description 7
- 210000000020 growth cone Anatomy 0.000 description 7
- 229940072221 immunoglobulins Drugs 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 229920001542 oligosaccharide Polymers 0.000 description 7
- 230000026731 phosphorylation Effects 0.000 description 7
- 238000006366 phosphorylation reaction Methods 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 208000008864 scrapie Diseases 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 210000002027 skeletal muscle Anatomy 0.000 description 7
- 238000013519 translation Methods 0.000 description 7
- 101710205625 Capsid protein p24 Proteins 0.000 description 6
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 6
- 208000037357 HIV infectious disease Diseases 0.000 description 6
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 6
- 101001016865 Homo sapiens Heat shock protein HSP 90-alpha Proteins 0.000 description 6
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 6
- 101710177166 Phosphoprotein Proteins 0.000 description 6
- 102000016611 Proteoglycans Human genes 0.000 description 6
- 108010067787 Proteoglycans Proteins 0.000 description 6
- 108091034057 RNA (poly(A)) Proteins 0.000 description 6
- 101710149279 Small delta antigen Proteins 0.000 description 6
- 102100022563 Tubulin polymerization-promoting protein Human genes 0.000 description 6
- WQZGKKKJIJFFOK-FPRJBGLDSA-N beta-D-galactose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-FPRJBGLDSA-N 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 206010014599 encephalitis Diseases 0.000 description 6
- 150000002270 gangliosides Chemical class 0.000 description 6
- 230000014509 gene expression Effects 0.000 description 6
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 6
- 230000005012 migration Effects 0.000 description 6
- 238000013508 migration Methods 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 230000007480 spreading Effects 0.000 description 6
- 238000003892 spreading Methods 0.000 description 6
- 230000000638 stimulation Effects 0.000 description 6
- 230000001629 suppression Effects 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 235000008521 threonine Nutrition 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 102000007590 Calpain Human genes 0.000 description 5
- 108010032088 Calpain Proteins 0.000 description 5
- 206010057248 Cell death Diseases 0.000 description 5
- 101710177291 Gag polyprotein Proteins 0.000 description 5
- JLXVRFDTDUGQEE-YFKPBYRVSA-N Gly-Arg Chemical group NCC(=O)N[C@H](C(O)=O)CCCN=C(N)N JLXVRFDTDUGQEE-YFKPBYRVSA-N 0.000 description 5
- 229930186217 Glycolipid Natural products 0.000 description 5
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 5
- 108010048209 Human Immunodeficiency Virus Proteins Proteins 0.000 description 5
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 5
- 102100039564 Leukosialin Human genes 0.000 description 5
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 5
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 5
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 5
- 102000000835 NK Cell Lectin-Like Receptor Subfamily B Human genes 0.000 description 5
- 108010001882 NK Cell Lectin-Like Receptor Subfamily B Proteins 0.000 description 5
- 108010066816 Polypeptide N-acetylgalactosaminyltransferase Proteins 0.000 description 5
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 5
- 238000009825 accumulation Methods 0.000 description 5
- 230000001154 acute effect Effects 0.000 description 5
- 230000005754 cellular signaling Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000004132 cross linking Methods 0.000 description 5
- 230000009089 cytolysis Effects 0.000 description 5
- 230000004069 differentiation Effects 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 238000006073 displacement reaction Methods 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 229920000669 heparin Polymers 0.000 description 5
- 229960002897 heparin Drugs 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 108010084553 jacalin Proteins 0.000 description 5
- 239000003226 mitogen Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004118 muscle contraction Effects 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 230000010349 pulsation Effects 0.000 description 5
- 241001529453 unidentified herpesvirus Species 0.000 description 5
- -1 β-D-galactose pyranose Chemical class 0.000 description 5
- 102000014914 Carrier Proteins Human genes 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 229920002971 Heparan sulfate Polymers 0.000 description 4
- 101000608935 Homo sapiens Leukosialin Proteins 0.000 description 4
- 101001098802 Homo sapiens Protein disulfide-isomerase A3 Proteins 0.000 description 4
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 4
- 208000006877 Insect Bites and Stings Diseases 0.000 description 4
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 4
- 241000282553 Macaca Species 0.000 description 4
- 101710125418 Major capsid protein Proteins 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- 102100036352 Protein disulfide-isomerase Human genes 0.000 description 4
- 102100037097 Protein disulfide-isomerase A3 Human genes 0.000 description 4
- 241000239226 Scorpiones Species 0.000 description 4
- 108091008874 T cell receptors Proteins 0.000 description 4
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 4
- 102000004357 Transferases Human genes 0.000 description 4
- 108090000992 Transferases Proteins 0.000 description 4
- 238000005054 agglomeration Methods 0.000 description 4
- MXWJVTOOROXGIU-UHFFFAOYSA-N atrazine Chemical compound CCNC1=NC(Cl)=NC(NC(C)C)=N1 MXWJVTOOROXGIU-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 108010005774 beta-Galactosidase Proteins 0.000 description 4
- 108091008324 binding proteins Proteins 0.000 description 4
- 230000034303 cell budding Effects 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 210000004292 cytoskeleton Anatomy 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 230000002950 deficient Effects 0.000 description 4
- 230000003111 delayed effect Effects 0.000 description 4
- 230000003292 diminished effect Effects 0.000 description 4
- 210000003979 eosinophil Anatomy 0.000 description 4
- 230000029142 excretion Effects 0.000 description 4
- 230000028023 exocytosis Effects 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000006317 isomerization reaction Methods 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 229910001425 magnesium ion Inorganic materials 0.000 description 4
- 230000009347 mechanical transmission Effects 0.000 description 4
- 238000007069 methylation reaction Methods 0.000 description 4
- 235000013336 milk Nutrition 0.000 description 4
- 239000008267 milk Substances 0.000 description 4
- 210000004080 milk Anatomy 0.000 description 4
- 230000011278 mitosis Effects 0.000 description 4
- 210000004165 myocardium Anatomy 0.000 description 4
- 230000003094 perturbing effect Effects 0.000 description 4
- 230000008488 polyadenylation Effects 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 238000003752 polymerase chain reaction Methods 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 235000004400 serine Nutrition 0.000 description 4
- 108091006024 signal transducing proteins Proteins 0.000 description 4
- 102000034285 signal transducing proteins Human genes 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 210000001541 thymus gland Anatomy 0.000 description 4
- 239000013598 vector Substances 0.000 description 4
- 208000035404 Autolysis Diseases 0.000 description 3
- 102000003930 C-Type Lectins Human genes 0.000 description 3
- 108090000342 C-Type Lectins Proteins 0.000 description 3
- YDNKGFDKKRUKPY-JHOUSYSJSA-N C16 ceramide Natural products CCCCCCCCCCCCCCCC(=O)N[C@@H](CO)[C@H](O)C=CCCCCCCCCCCCCC YDNKGFDKKRUKPY-JHOUSYSJSA-N 0.000 description 3
- 108010078791 Carrier Proteins Proteins 0.000 description 3
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 3
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 3
- 108091006146 Channels Proteins 0.000 description 3
- 108010047041 Complementarity Determining Regions Proteins 0.000 description 3
- 208000005156 Dehydration Diseases 0.000 description 3
- 206010061818 Disease progression Diseases 0.000 description 3
- 241000713730 Equine infectious anemia virus Species 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 206010020751 Hypersensitivity Diseases 0.000 description 3
- 108700002232 Immediate-Early Genes Proteins 0.000 description 3
- 206010061598 Immunodeficiency Diseases 0.000 description 3
- 208000029462 Immunodeficiency disease Diseases 0.000 description 3
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 3
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 3
- 108010002352 Interleukin-1 Proteins 0.000 description 3
- 102000009112 Mannose-Binding Lectin Human genes 0.000 description 3
- 108010087870 Mannose-Binding Lectin Proteins 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 3
- CRJGESKKUOMBCT-VQTJNVASSA-N N-acetylsphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@H](CO)NC(C)=O CRJGESKKUOMBCT-VQTJNVASSA-N 0.000 description 3
- 102100033457 NF-kappa-B inhibitor beta Human genes 0.000 description 3
- 101710204094 NF-kappa-B inhibitor beta Proteins 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- 108700026244 Open Reading Frames Proteins 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 108090000704 Tubulin Proteins 0.000 description 3
- 102000004243 Tubulin Human genes 0.000 description 3
- 108020005202 Viral DNA Proteins 0.000 description 3
- 108020000999 Viral RNA Proteins 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 208000026935 allergic disease Diseases 0.000 description 3
- 230000007815 allergy Effects 0.000 description 3
- 230000030741 antigen processing and presentation Effects 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 229940106189 ceramide Drugs 0.000 description 3
- ZVEQCJWYRWKARO-UHFFFAOYSA-N ceramide Natural products CCCCCCCCCCCCCCC(O)C(=O)NC(CO)C(O)C=CCCC=C(C)CCCCCCCCC ZVEQCJWYRWKARO-UHFFFAOYSA-N 0.000 description 3
- 229930183167 cerebroside Natural products 0.000 description 3
- 150000001784 cerebrosides Chemical class 0.000 description 3
- 238000005352 clarification Methods 0.000 description 3
- 230000001054 cortical effect Effects 0.000 description 3
- 102000003675 cytokine receptors Human genes 0.000 description 3
- 108010057085 cytokine receptors Proteins 0.000 description 3
- 230000001461 cytolytic effect Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 230000005750 disease progression Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 230000007813 immunodeficiency Effects 0.000 description 3
- 102000006495 integrins Human genes 0.000 description 3
- 108010044426 integrins Proteins 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 239000006166 lysate Substances 0.000 description 3
- 235000018977 lysine Nutrition 0.000 description 3
- 210000004779 membrane envelope Anatomy 0.000 description 3
- 230000037191 muscle physiology Effects 0.000 description 3
- VVGIYYKRAMHVLU-UHFFFAOYSA-N newbouldiamide Natural products CCCCCCCCCCCCCCCCCCCC(O)C(O)C(O)C(CO)NC(=O)CCCCCCCCCCCCCCCCC VVGIYYKRAMHVLU-UHFFFAOYSA-N 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000001823 pruritic effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 230000003252 repetitive effect Effects 0.000 description 3
- 230000000284 resting effect Effects 0.000 description 3
- 210000001995 reticulocyte Anatomy 0.000 description 3
- 210000002235 sarcomere Anatomy 0.000 description 3
- 230000028043 self proteolysis Effects 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 229910001415 sodium ion Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 150000003588 threonines Chemical class 0.000 description 3
- 238000010361 transduction Methods 0.000 description 3
- 230000026683 transduction Effects 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- QGVLYPPODPLXMB-UBTYZVCOSA-N (1aR,1bS,4aR,7aS,7bS,8R,9R,9aS)-4a,7b,9,9a-tetrahydroxy-3-(hydroxymethyl)-1,1,6,8-tetramethyl-1,1a,1b,4,4a,7a,7b,8,9,9a-decahydro-5H-cyclopropa[3,4]benzo[1,2-e]azulen-5-one Chemical compound C1=C(CO)C[C@]2(O)C(=O)C(C)=C[C@H]2[C@@]2(O)[C@H](C)[C@@H](O)[C@@]3(O)C(C)(C)[C@H]3[C@@H]21 QGVLYPPODPLXMB-UBTYZVCOSA-N 0.000 description 2
- NWGZOALPWZDXNG-LURJTMIESA-N (2s)-5-(diaminomethylideneamino)-2-(dimethylamino)pentanoic acid Chemical compound CN(C)[C@H](C(O)=O)CCCNC(N)=N NWGZOALPWZDXNG-LURJTMIESA-N 0.000 description 2
- 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 2
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 2
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 2
- 108700028369 Alleles Proteins 0.000 description 2
- 102000004145 Annexin A1 Human genes 0.000 description 2
- 108090000663 Annexin A1 Proteins 0.000 description 2
- 108010017088 CCR5 Receptors Proteins 0.000 description 2
- 102000004274 CCR5 Receptors Human genes 0.000 description 2
- 101100454807 Caenorhabditis elegans lgg-1 gene Proteins 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 102000005600 Cathepsins Human genes 0.000 description 2
- 108010084457 Cathepsins Proteins 0.000 description 2
- 102000052603 Chaperonins Human genes 0.000 description 2
- 108050000299 Chemokine receptor Proteins 0.000 description 2
- 102000009410 Chemokine receptor Human genes 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 2
- 108010036949 Cyclosporine Proteins 0.000 description 2
- 206010011968 Decreased immune responsiveness Diseases 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- 241000283073 Equus caballus Species 0.000 description 2
- 102000004961 Furin Human genes 0.000 description 2
- 108090001126 Furin Proteins 0.000 description 2
- 102000007563 Galectins Human genes 0.000 description 2
- 108010046569 Galectins Proteins 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 101710113864 Heat shock protein 90 Proteins 0.000 description 2
- 108010022901 Heparin Lyase Proteins 0.000 description 2
- 108010019372 Heterogeneous-Nuclear Ribonucleoproteins Proteins 0.000 description 2
- 102000006479 Heterogeneous-Nuclear Ribonucleoproteins Human genes 0.000 description 2
- 101000979249 Homo sapiens Neuromodulin Proteins 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 2
- 208000032420 Latent Infection Diseases 0.000 description 2
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 2
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 2
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 2
- BKAYIFDRRZZKNF-VIFPVBQESA-N N-acetylcarnosine Chemical compound CC(=O)NCCC(=O)N[C@H](C(O)=O)CC1=CN=CN1 BKAYIFDRRZZKNF-VIFPVBQESA-N 0.000 description 2
- 102100023206 Neuromodulin Human genes 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102100026918 Phospholipase A2 Human genes 0.000 description 2
- 102000015439 Phospholipases Human genes 0.000 description 2
- 108010064785 Phospholipases Proteins 0.000 description 2
- 108010058864 Phospholipases A2 Proteins 0.000 description 2
- 108091036407 Polyadenylation Proteins 0.000 description 2
- 102100026534 Procathepsin L Human genes 0.000 description 2
- 102000006437 Proprotein Convertases Human genes 0.000 description 2
- 108010044159 Proprotein Convertases Proteins 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 101800001690 Transmembrane protein gp41 Proteins 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 description 2
- 206010058874 Viraemia Diseases 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 208000034615 apoptosis-related disease Diseases 0.000 description 2
- 150000001483 arginine derivatives Chemical class 0.000 description 2
- 230000002238 attenuated effect Effects 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 230000008335 axon cargo transport Effects 0.000 description 2
- 238000005452 bending Methods 0.000 description 2
- 210000000601 blood cell Anatomy 0.000 description 2
- 238000006664 bond formation reaction Methods 0.000 description 2
- 229910001424 calcium ion Inorganic materials 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000004656 cell transport Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 229960001265 ciclosporin Drugs 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 230000006854 communication Effects 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 210000003674 cytoplasmic vesicle Anatomy 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 230000030609 dephosphorylation Effects 0.000 description 2
- 238000006209 dephosphorylation reaction Methods 0.000 description 2
- 230000001687 destabilization Effects 0.000 description 2
- 230000000368 destabilizing effect Effects 0.000 description 2
- 239000003599 detergent Substances 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 208000037771 disease arising from reactivation of latent virus Diseases 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 238000004880 explosion Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 210000001650 focal adhesion Anatomy 0.000 description 2
- 150000002339 glycosphingolipids Chemical class 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 108010038082 heparin proteoglycan Proteins 0.000 description 2
- 210000005260 human cell Anatomy 0.000 description 2
- 235000020256 human milk Nutrition 0.000 description 2
- 210000004251 human milk Anatomy 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000001524 infective effect Effects 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000030214 innervation Effects 0.000 description 2
- 239000002555 ionophore Substances 0.000 description 2
- 230000000236 ionophoric effect Effects 0.000 description 2
- 229960000310 isoleucine Drugs 0.000 description 2
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N lysine Chemical compound NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 150000002669 lysines Chemical class 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 210000001161 mammalian embryo Anatomy 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 230000006540 mitochondrial respiration Effects 0.000 description 2
- 230000001459 mortal effect Effects 0.000 description 2
- 210000002161 motor neuron Anatomy 0.000 description 2
- 229940105132 myristate Drugs 0.000 description 2
- 229950006780 n-acetylglucosamine Drugs 0.000 description 2
- 230000007514 neuronal growth Effects 0.000 description 2
- 230000021962 pH elevation Effects 0.000 description 2
- 230000008506 pathogenesis Effects 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- QGVLYPPODPLXMB-QXYKVGAMSA-N phorbol Natural products C[C@@H]1[C@@H](O)[C@]2(O)[C@H]([C@H]3C=C(CO)C[C@@]4(O)[C@H](C=C(C)C4=O)[C@@]13O)C2(C)C QGVLYPPODPLXMB-QXYKVGAMSA-N 0.000 description 2
- 235000021317 phosphate Nutrition 0.000 description 2
- 230000008884 pinocytosis Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 108010028075 procathepsin L Proteins 0.000 description 2
- 230000004853 protein function Effects 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 108090000064 retinoic acid receptors Proteins 0.000 description 2
- 102000003702 retinoic acid receptors Human genes 0.000 description 2
- 230000001177 retroviral effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 108010087686 src-Family Kinases Proteins 0.000 description 2
- 102000009076 src-Family Kinases Human genes 0.000 description 2
- 239000003270 steroid hormone Substances 0.000 description 2
- 230000004936 stimulating effect Effects 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- 208000010648 susceptibility to HIV infection Diseases 0.000 description 2
- 210000002504 synaptic vesicle Anatomy 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 230000005945 translocation Effects 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000007502 viral entry Effects 0.000 description 2
- 229960004854 viral vaccine Drugs 0.000 description 2
- 210000002845 virion Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QCUPYFTWJOZAOB-HWKANZROSA-N (e)-n-carbamoyl-2-ethylbut-2-enamide Chemical compound CC\C(=C/C)C(=O)NC(N)=O QCUPYFTWJOZAOB-HWKANZROSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- CNWINRVXAYPOMW-FCNJXWMTSA-N 1-stearoyl-2-arachidonoyl-sn-glycero-3-phospho-1D-myo-inositol 4,5-biphosphate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)O[C@H](COC(=O)CCCCCCCCCCCCCCCCC)COP(O)(=O)O[C@@H]1[C@H](O)[C@H](O)[C@@H](OP(O)(O)=O)[C@H](OP(O)(O)=O)[C@H]1O CNWINRVXAYPOMW-FCNJXWMTSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- 108020004565 5.8S Ribosomal RNA Proteins 0.000 description 1
- GOZMBJCYMQQACI-UHFFFAOYSA-N 6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one;dihydrochloride Chemical compound Cl.Cl.C=1OC2=CC(C)=C(C)C=C2C(=O)C=1CN(C)CCN(C)CC(C1=CC=CC=C11)=CN1C1=CC=CC(C(F)(F)F)=C1 GOZMBJCYMQQACI-UHFFFAOYSA-N 0.000 description 1
- 229940124321 AIDS medicine Drugs 0.000 description 1
- 108091006112 ATPases Proteins 0.000 description 1
- 108020005176 AU Rich Elements Proteins 0.000 description 1
- 102000057290 Adenosine Triphosphatases Human genes 0.000 description 1
- 244000251953 Agaricus brunnescens Species 0.000 description 1
- 102100027211 Albumin Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 241001135972 Aleutian mink disease virus Species 0.000 description 1
- 102000005666 Apolipoprotein A-I Human genes 0.000 description 1
- 108010059886 Apolipoprotein A-I Proteins 0.000 description 1
- 102000019260 B-Cell Antigen Receptors Human genes 0.000 description 1
- 108010012919 B-Cell Antigen Receptors Proteins 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 102100032912 CD44 antigen Human genes 0.000 description 1
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 description 1
- 101150099575 CDC37 gene Proteins 0.000 description 1
- 108010034291 COOH-terminal signal transamidase Proteins 0.000 description 1
- 108050006947 CXC Chemokine Proteins 0.000 description 1
- 102000019388 CXC chemokine Human genes 0.000 description 1
- 108010061299 CXCR4 Receptors Proteins 0.000 description 1
- 102000012000 CXCR4 Receptors Human genes 0.000 description 1
- 101100005789 Caenorhabditis elegans cdk-4 gene Proteins 0.000 description 1
- 101100454808 Caenorhabditis elegans lgg-2 gene Proteins 0.000 description 1
- 101100217502 Caenorhabditis elegans lgg-3 gene Proteins 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 241000713756 Caprine arthritis encephalitis virus Species 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- 102000003908 Cathepsin D Human genes 0.000 description 1
- 108090000258 Cathepsin D Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 108050001186 Chaperonin Cpn60 Proteins 0.000 description 1
- 108700021022 Chaperonins Proteins 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- 102000011412 Complement 3d Receptors Human genes 0.000 description 1
- 108010023729 Complement 3d Receptors Proteins 0.000 description 1
- 102100035436 Complement factor D Human genes 0.000 description 1
- 241000711573 Coronaviridae Species 0.000 description 1
- 241000557626 Corvus corax Species 0.000 description 1
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 description 1
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 description 1
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 241000724252 Cucumber mosaic virus Species 0.000 description 1
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 230000006820 DNA synthesis Effects 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- MQJKPEGWNLWLTK-UHFFFAOYSA-N Dapsone Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 MQJKPEGWNLWLTK-UHFFFAOYSA-N 0.000 description 1
- 208000001490 Dengue Diseases 0.000 description 1
- 206010012310 Dengue fever Diseases 0.000 description 1
- 102000007260 Deoxyribonuclease I Human genes 0.000 description 1
- 108010008532 Deoxyribonuclease I Proteins 0.000 description 1
- 101000609814 Dictyostelium discoideum Protein disulfide-isomerase 1 Proteins 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 1
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 description 1
- 206010014596 Encephalitis Japanese B Diseases 0.000 description 1
- 102100039715 Endogenous retrovirus group K member 6 Gag polyprotein Human genes 0.000 description 1
- 102100039328 Endoplasmin Human genes 0.000 description 1
- 208000000832 Equine Encephalomyelitis Diseases 0.000 description 1
- 102100038595 Estrogen receptor Human genes 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- 241000710831 Flavivirus Species 0.000 description 1
- 241000204348 Fungia Species 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 102100036858 GPI-anchor transamidase Human genes 0.000 description 1
- 108010001498 Galectin 1 Proteins 0.000 description 1
- OWOFCNWTMWOOJJ-WDSKDSINSA-N Gln-Glu Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(O)=O OWOFCNWTMWOOJJ-WDSKDSINSA-N 0.000 description 1
- 102000028180 Glycophorins Human genes 0.000 description 1
- 108091005250 Glycophorins Proteins 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 108700023372 Glycosyltransferases Proteins 0.000 description 1
- 102000051366 Glycosyltransferases Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 208000007521 HIV Seropositivity Diseases 0.000 description 1
- 101710182268 Heat shock protein HSP 90 Proteins 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 241000520223 Helice Species 0.000 description 1
- 208000009889 Herpes Simplex Diseases 0.000 description 1
- 102100028895 Heterogeneous nuclear ribonucleoprotein M Human genes 0.000 description 1
- SQUHHTBVTRBESD-UHFFFAOYSA-N Hexa-Ac-myo-Inositol Natural products CC(=O)OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O SQUHHTBVTRBESD-UHFFFAOYSA-N 0.000 description 1
- 101100005713 Homo sapiens CD4 gene Proteins 0.000 description 1
- 101000868273 Homo sapiens CD44 antigen Proteins 0.000 description 1
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 1
- 101000920686 Homo sapiens Erythropoietin Proteins 0.000 description 1
- 101000839073 Homo sapiens Heterogeneous nuclear ribonucleoprotein M Proteins 0.000 description 1
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 1
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 description 1
- 101001114059 Homo sapiens Protein-arginine deiminase type-1 Proteins 0.000 description 1
- 108091008585 IP3 receptors Proteins 0.000 description 1
- 102000007640 Inositol 1,4,5-Trisphosphate Receptors Human genes 0.000 description 1
- 102100026720 Interferon beta Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 241000726306 Irus Species 0.000 description 1
- 201000005807 Japanese encephalitis Diseases 0.000 description 1
- 241000710842 Japanese encephalitis virus Species 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- 125000000769 L-threonyl group Chemical group [H]N([H])[C@]([H])(C(=O)[*])[C@](O[H])(C([H])([H])[H])[H] 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 241000710789 Lactate dehydrogenase-elevating virus Species 0.000 description 1
- 108010005832 Leukosialin Proteins 0.000 description 1
- 102100029185 Low affinity immunoglobulin gamma Fc region receptor III-B Human genes 0.000 description 1
- 208000008771 Lymphadenopathy Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- PBOUVYGPDSARIS-IUCAKERBSA-N Met-Leu Chemical compound CSCC[C@H](N)C(=O)N[C@H](C(O)=O)CC(C)C PBOUVYGPDSARIS-IUCAKERBSA-N 0.000 description 1
- 102100023174 Methionine aminopeptidase 2 Human genes 0.000 description 1
- 108090000192 Methionyl aminopeptidases Proteins 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 229930191564 Monensin Natural products 0.000 description 1
- GAOZTHIDHYLHMS-UHFFFAOYSA-N Monensin A Natural products O1C(CC)(C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CCC1C(O1)(C)CCC21CC(O)C(C)C(C(C)C(OC)C(C)C(O)=O)O2 GAOZTHIDHYLHMS-UHFFFAOYSA-N 0.000 description 1
- 102000007474 Multiprotein Complexes Human genes 0.000 description 1
- 108010085220 Multiprotein Complexes Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- OVRNDRQMDRJTHS-CBQIKETKSA-N N-Acetyl-D-Galactosamine Chemical compound CC(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@H](O)[C@@H]1O OVRNDRQMDRJTHS-CBQIKETKSA-N 0.000 description 1
- MBLBDJOUHNCFQT-UHFFFAOYSA-N N-acetyl-D-galactosamine Natural products CC(=O)NC(C=O)C(O)C(O)C(O)CO MBLBDJOUHNCFQT-UHFFFAOYSA-N 0.000 description 1
- 101710167853 N-methyltransferase Proteins 0.000 description 1
- 101100084040 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) ppi-1 gene Proteins 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 1
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 1
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 description 1
- 208000001388 Opportunistic Infections Diseases 0.000 description 1
- 101800004803 Papain-like protease Proteins 0.000 description 1
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 1
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 1
- 102100020739 Peptidyl-prolyl cis-trans isomerase FKBP4 Human genes 0.000 description 1
- 101710147152 Peptidyl-prolyl cis-trans isomerase FKBP4 Proteins 0.000 description 1
- 241000709664 Picornaviridae Species 0.000 description 1
- 102100026090 Polyadenylate-binding protein 1 Human genes 0.000 description 1
- 101710139643 Polyadenylate-binding protein 1 Proteins 0.000 description 1
- 229920001744 Polyaldehyde Polymers 0.000 description 1
- 102100020947 Polypeptide N-acetylgalactosaminyltransferase 1 Human genes 0.000 description 1
- 229920000388 Polyphosphate Polymers 0.000 description 1
- 241001135989 Porcine reproductive and respiratory syndrome virus Species 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000055027 Protein Methyltransferases Human genes 0.000 description 1
- 108700040121 Protein Methyltransferases Proteins 0.000 description 1
- 102000006478 Protein Phosphatase 2 Human genes 0.000 description 1
- 108010058956 Protein Phosphatase 2 Proteins 0.000 description 1
- 101710150344 Protein Rev Proteins 0.000 description 1
- 101710106234 Protein disulfide-isomerase A5 Proteins 0.000 description 1
- 102100037061 Protein disulfide-isomerase A6 Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 102100023222 Protein-arginine deiminase type-1 Human genes 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 241000125945 Protoparvovirus Species 0.000 description 1
- 230000004570 RNA-binding Effects 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 241000725643 Respiratory syncytial virus Species 0.000 description 1
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 1
- 102100033912 Retinoic acid receptor gamma Human genes 0.000 description 1
- 108020001027 Ribosomal DNA Proteins 0.000 description 1
- 108090000904 Ribosomal protein S2 Proteins 0.000 description 1
- 102000004339 Ribosomal protein S2 Human genes 0.000 description 1
- 108050008861 SH3 domains Proteins 0.000 description 1
- 102000000395 SH3 domains Human genes 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 101100178269 Schizosaccharomyces pombe (strain 972 / ATCC 24843) hob1 gene Proteins 0.000 description 1
- 108090000184 Selectins Proteins 0.000 description 1
- 102000003800 Selectins Human genes 0.000 description 1
- WOUIMBGNEUWXQG-VKHMYHEASA-N Ser-Gly Chemical compound OC[C@H](N)C(=O)NCC(O)=O WOUIMBGNEUWXQG-VKHMYHEASA-N 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 241000356642 Sole virus Species 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 description 1
- 101710088580 Stromal cell-derived factor 1 Proteins 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
- 230000006052 T cell proliferation Effects 0.000 description 1
- 230000005867 T cell response Effects 0.000 description 1
- 241000255632 Tabanus atratus Species 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- 101800001530 Thymosin alpha Proteins 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 108700019146 Transgenes Proteins 0.000 description 1
- 241000869417 Trematodes Species 0.000 description 1
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 1
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 1
- 102000014384 Type C Phospholipases Human genes 0.000 description 1
- 108010079194 Type C Phospholipases Proteins 0.000 description 1
- 101710100170 Unknown protein Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000010094 Visna Diseases 0.000 description 1
- 208000003152 Yellow Fever Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000002547 anomalous effect Effects 0.000 description 1
- 230000000919 anti-host Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000002788 anti-peptide Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- 150000001484 arginines Chemical class 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 108010089975 arginyl-glycyl-aspartyl-serine Proteins 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 150000001510 aspartic acids Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- VFBJEDFCUUCMBQ-UHFFFAOYSA-O azanium;sodium;antimony(3+);oxygen(2-);tungsten Chemical compound [NH4+].[O-2].[Na+].[Sb+3].[W] VFBJEDFCUUCMBQ-UHFFFAOYSA-O 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 102000015736 beta 2-Microglobulin Human genes 0.000 description 1
- 108010081355 beta 2-Microglobulin Proteins 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 1
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 description 1
- 230000008436 biogenesis Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000007910 cell fusion Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 230000005889 cellular cytotoxicity Effects 0.000 description 1
- 230000008614 cellular interaction Effects 0.000 description 1
- 241000902900 cellular organisms Species 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002975 chemoattractant Substances 0.000 description 1
- 108091008690 chemoreceptors Proteins 0.000 description 1
- 230000003399 chemotactic effect Effects 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 229910001919 chlorite Inorganic materials 0.000 description 1
- 229910052619 chlorite group Inorganic materials 0.000 description 1
- QBWCMBCROVPCKQ-UHFFFAOYSA-N chlorous acid Chemical compound OCl=O QBWCMBCROVPCKQ-UHFFFAOYSA-N 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000008045 co-localization Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000008094 contradictory effect Effects 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 150000001913 cyanates Chemical class 0.000 description 1
- 210000005220 cytoplasmic tail Anatomy 0.000 description 1
- 230000030498 cytoplasmic translation Effects 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 210000001787 dendrite Anatomy 0.000 description 1
- 208000025729 dengue disease Diseases 0.000 description 1
- 238000000586 desensitisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000007646 directional migration Effects 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- JGMOKGBVKVMRFX-HQZYFCCVSA-N dydrogesterone Chemical compound C1=CC2=CC(=O)CC[C@@]2(C)[C@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 JGMOKGBVKVMRFX-HQZYFCCVSA-N 0.000 description 1
- 230000005684 electric field Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000003241 endoproteolytic effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical compound NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 108700025906 fos Genes Proteins 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- ZXQYGBMAQZUVMI-GCMPRSNUSA-N gamma-cyhalothrin Chemical compound CC1(C)[C@@H](\C=C(/Cl)C(F)(F)F)[C@H]1C(=O)O[C@H](C#N)C1=CC=CC(OC=2C=CC=CC=2)=C1 ZXQYGBMAQZUVMI-GCMPRSNUSA-N 0.000 description 1
- 102000054767 gene variant Human genes 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 230000001295 genetical effect Effects 0.000 description 1
- 102000034238 globular proteins Human genes 0.000 description 1
- 108091005896 globular proteins Proteins 0.000 description 1
- 108010017007 glucose-regulated proteins Proteins 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002307 glutamic acids Chemical class 0.000 description 1
- 150000002333 glycines Chemical class 0.000 description 1
- 108700014210 glycosyltransferase activity proteins Proteins 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 230000000423 heterosexual effect Effects 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 230000000652 homosexual effect Effects 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 102000044890 human EPO Human genes 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 210000005061 intracellular organelle Anatomy 0.000 description 1
- 230000020991 intracellular pH elevation Effects 0.000 description 1
- 230000010189 intracellular transport Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 210000001821 langerhans cell Anatomy 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical group 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 241000238565 lobster Species 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000004216 mammary stem cell Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000001806 memory b lymphocyte Anatomy 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 108091005592 methylated proteins Proteins 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229960005358 monensin Drugs 0.000 description 1
- GAOZTHIDHYLHMS-KEOBGNEYSA-N monensin A Chemical compound C([C@@](O1)(C)[C@H]2CC[C@@](O2)(CC)[C@H]2[C@H](C[C@@H](O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C[C@@]21C[C@H](O)[C@@H](C)[C@@H]([C@@H](C)[C@@H](OC)[C@H](C)C(O)=O)O2 GAOZTHIDHYLHMS-KEOBGNEYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 230000004220 muscle function Effects 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 230000004719 natural immunity Effects 0.000 description 1
- 108700004028 nef Genes Proteins 0.000 description 1
- 101150023385 nef gene Proteins 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 230000003988 neural development Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002241 neurite Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 108010010765 nuclear factor-jun Proteins 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 238000006384 oligomerization reaction Methods 0.000 description 1
- 230000005868 ontogenesis Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 230000005551 perinatal transmission Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000000505 pernicious effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003907 phosphatidylinositol monophosphates Chemical class 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 108091005981 phosphorylated proteins Proteins 0.000 description 1
- 230000010399 physical interaction Effects 0.000 description 1
- 229920000333 poly(propyleneimine) Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001205 polyphosphate Substances 0.000 description 1
- 235000011176 polyphosphates Nutrition 0.000 description 1
- 210000002729 polyribosome Anatomy 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 210000001176 projection neuron Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000018299 prostration Diseases 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 210000003660 reticulum Anatomy 0.000 description 1
- 108091008726 retinoic acid receptors α Proteins 0.000 description 1
- 108091008760 retinoic acid receptors γ Proteins 0.000 description 1
- 229940064914 retrovir Drugs 0.000 description 1
- 238000010839 reverse transcription Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 102220240796 rs553605556 Human genes 0.000 description 1
- 108010038196 saccharide-binding proteins Proteins 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 150000003355 serines Chemical class 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- GECHUMIMRBOMGK-UHFFFAOYSA-N sulfapyridine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=CC=N1 GECHUMIMRBOMGK-UHFFFAOYSA-N 0.000 description 1
- 229960002211 sulfapyridine Drugs 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 230000017960 syncytium formation Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 210000003412 trans-golgi network Anatomy 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 210000000264 venule Anatomy 0.000 description 1
- 231100000925 very toxic Toxicity 0.000 description 1
- 230000007444 viral RNA synthesis Effects 0.000 description 1
- 230000007501 viral attachment Effects 0.000 description 1
- 230000008478 viral entry into host cell Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000006656 viral protein synthesis Effects 0.000 description 1
- 230000006490 viral transcription Effects 0.000 description 1
- 230000002747 voluntary effect Effects 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- 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
- C12N2740/00—Reverse transcribing RNA viruses
- C12N2740/00011—Details
- C12N2740/10011—Retroviridae
- C12N2740/16011—Human Immunodeficiency Virus, HIV
- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Definitions
- FOLDINDS SAFE VACCINES, UNIVERSAL ANTIMICROBIAL MEANS, MAD COW END.
- ⁇ 4.Cytokine receptors are responsible for 1st entry of HIV viruses into the monocytes/macrophages during their movement 16
- Intracellular A-particles are ciear reason of false viral presences after 1st contamination (seropositives) 25
- Part VI Practical consequences of Parts I-V. 46
- Part X Net Solution of the Process of Formation of Priones: Primary Cause of Mad Cow and Creutzfeldt- Jacob diseases is Artificial Dissociation of "Du-2T" peptides-60 ANNEX.
- Part I A. Universal Propagation of Signal from Plasma Membrane to Nucleus. Increase of pH ⁇ lncreased Synthesis of Cathepsin L (CL) ⁇ Liberation of
- Part XI Practical consequences of Parts VII-X and Annex 74
- CCR5-2 inactive ⁇ -chemokine receptors
- cytokines are the intermediates during the signallings leading to the migrations and adhesions of contaminated macrophages with corresponding viral protein synthesis (at
- the nonproductive 1st HIV entry takes place during the macrophage cell movement with endocytosis, with u ⁇ integrated replicated viral DNAs, with heterogeneity (although limited) of DNAs and corresponding proteins, with presence of intracystemal A-particles (lAP) and with the pattern of antibodies against the corresponding heterogeneous viral proteins.
- lAP intracystemal A-particles
- Such lAPs justly, make the very weak virus pseudocontamination of other cells due to RNA and reverse tra ⁇ scriptase that they contain.
- the gag coat of such preudoparticles is assembled in cytoplasme and their RNAs are not transported with ribosomes to the plasma membrane.
- nef protein is indispensable for such necessary heterogeneity after the DNA reverse transcription.
- another nef protein function is an attenuation of the cellular machinery activity that, logically, must permit a better presentation of endogenous secretable viral ⁇ o ⁇ - env molecules to MHC-I molecules.
- the long term infant AIDS must be due to very small dozes transmitted by parasites or due to bad hygiene because of AIDS-sick nearby parents.
- the macrophage tropic clones have the best (corresponding to macrophages) carbohydrate pattern and contaminate them at 1st contamination. At the 2nd contamination, also the macrophage tropic clones contaminate, with help of antibodies already, the macrophages and (in smaller degree) lymphocytes T4. But principally, only the macrophages produce in vivo, by budding, the new viral particles, but the T-cells undergo the apoptosis with syncytium creation. The macrophages well phagocytize (regularly) cells during apoptosis, so the contaminated T4 cells are destroyed until host death by relatively small groups that are not well visible.
- the signaling specific perturbation from outside with charged antiviral antibodies or an elimination of the anti-envelope antibodies clones with, also charged, idiotypic antibodies (against a ⁇ ti- envelope antibodies) must be successful.
- Two necessary types of HIV consecutive contaminations in vivo must also take place during only strong artificial contamination where anti-envelope antibodies meet the yet noneliminated introduced active viral particles, confirming the general strategy.
- the HlV-2 restricted contaminations are due to weaker variability of viral proteins at 1st contamination and larger differences between host and virus carbohydrate patterns. Generalizations for other viruses are evident.
- the 1st nonproductive contamination, also with utilization of cell motility, must be, for example, used by herpes viruses and the antibody-dependent enhancement is a property of viruses of a number of Families.
- PPI peptidyl-prolyl isomerase
- Du-2T- like proteins A real existence of these Du-2T- like proteins is proved in the case of IgG, Fc receptors and receptors for antigen and also for MHC molecules class I .
- the detailed mechanism of interactions between MHC- 1 molecules and T ceil receptor (TCR) is resolved (with "Du-2T”s, concrete carbohydrate chain interactions, special /justly!/ destabilizing charges in intramembranous domains of all components of TCR).
- Du-2T concrete carbohydrate chain interactions, special /justly!/ destabilizing charges in intramembranous domains of all components of TCR).
- the VERY important allotype specificity between TCR and MHC molecules is determined by common oloqocarbohydrates.
- Du-2T Mad Cow or Creutzfeldt-Jacob. Also the dissociation of these proteins "Du-2T” is the among of action of parasites: like viruses, bacteria, protozoans, mushrooms, during complement action, cell lysis, aggregation of proteins in solutions (as blood). So even a simple introduction of these "Du-2T” eliminates these grave processes. It is proved that Erp6l is not the chaperon but the vesicular Phospholipase C- .
- ANNEX basic foundation of VI -X.
- Ca and phosphatidylinositol phosphate derivatives propagate by diffusion until nucleus.
- This pH increase induces an increase of protein synthesis on ribosomes, CLs included, making the part of them free from rRNA attachment in cytoplasm (previous stock).
- Such free CL make autoactivation with activation of ribosomes by limited proteolysis of particular proteins of ribosomes and liberate (par limited proteolysis) other proteins (of signal machinery) also attached to rRNA with help of asymmetric dimethylarginine in sequences GR at protein . extremities.
- the alkaline phosphatase helps to such hydrolysis in eliminating the protective phosphorylation by casein kinase I (CK-I).
- Such detached molecules help to reconstruct, (without any transcription, translation and transport of proteins) the vesicular obligatory vectorial transport machinery (heart of each complete cell signal).
- the nuclear factors detached at the same time (by CL), activate the immediate-early genes, provoking the following chain of genes activations.
- the stock complex Rel: p105(p50)/p65(RelA)/lkB- ⁇ waits the signal in cytoplasm, being activated, firstly, by CL.
- EA Primary Nucleotide Structures of important proteins and the mechanism of process of the special Universal transduction of the signal from plasma membrane to nucleus. The serious proves for clear reality of the stocking of different important proteins are found in convergence with a number of their primary nucleotide sequences. An insitent presence of sequences GR at extremities of these proteins and their absence at other parts show the sites of their attachment to rRNA in ribosomes
- the interior unproteolysable regions of the actins and bFGF, with sequence GR correlate with their exceptional protections with Mg ions and heparin sulfate correspondingly.
- the persistent presence of stop codons upstream of 5'-end of open reading frame stabilizes the mRNA, that., justly, coincides with prolongated time of stocking between signals in GO or after phase Gl.
- the increased rate of a metabolism for nonstocked forms of some signalling proteins correlates with particular compartmentalizations (as growth cone or cell periphery) of their corresponding ribosomes directed by particular modifications of their present mRNA!
- Part XI From general Universal proof of protein Foldings, functionings and recognitions and consequently the action of viruses (and also bacteria, protozoans and machrooms) with help of Little Protein (Du-2T- like peptides), one can use them as
- apoptosis Due to established molecular origin of the apoptosis (end of the stock of the proteins of the transport cell machinery and the hydrolysis of the phosphatidylinositol 4,5-bisphsphate /PIP 2 / par functional /that was proved here/ PI-PLC- ⁇ /vesicular/), one can utilise the derivatives of PIP g against state of clinical death and coma. Also in accepting that the sleep is the partial reversible apoptosis of cells of the system of cyclic neurons in superior brain (determining conscience), one can utilize the substances that partially disrupt the vesicle transport system of such neurons as cyanates as hypnotics.
- T-cell polyclonal activators and B-cell mitogens can act only (justly) at 2nd stage.
- Table 1 Spectrum of the subclasses and classes of immunoglobulins serves to determine a sequence of events after the HIV contamination in vivo /1/.
- gag (pol) increased quantity of repetitions of the antigen introduction lgG4,lgE (lgG2,lgG3)
- gag (pol) increased quantity of repetitions of the antigen lgG4,lgE- hemophiliacs introduction gag p55 often lgG4 subclass synthesis of p55 de novo with several antibody
- Short-circuit is the activation, proliferation and differentiation of the B- cells by anti-gp4l and anti-gp120 (anti-MHC-I) antibodies instead of the T- cells in 2nd meeting.
- anti-MHC-I anti-MHC-I antibodies
- the entry of the virus with help of the cell motility takes place only at 1st entry. It is found that at the 1st stage, only a small quantity of the monocytes is contaminated hi. Logically, it must be the motile monocytes because the de novo expression of the special adhesion molecules in the particular organ enables the contaminated by lenti viruses monocytes (outside the organs) to be inside the organs /8-11/ ("Troyan horse" model /12/) and only the virus infected macrophages (monocytes) moving from the blood, penetrated into the brain /10.11/ and other tissues /11/.
- the macrophages, contaminated with SIV (simian immunodeficiency virus) were found only around small venules /13/ (It means: on the way). Moreover, the virus entry into central nervous system takes place early in infections /10.13/ that confirms a contamination of the moving at 1st stage macrophages. In confirmation , the inoculated, in brain, HIV does not produce here the contaminated macrophages /9/.
- the lesions in target organs for different lentiviruses are similar /8/.
- contamination of the motile monocytes/macrophages is happen due to the rearward migration of the cross-linked endogeneous proteins on the dorsal surface with the consequent endocytosis /14,15/.
- Such directed migration is coordinated with the consecutive contractions ("centripetal movements") of the microfilament sheath in direction of the nucleus ("waves of
- TNF- ⁇ activation par env gpt20 proteins of the secretion of cytokines: TNF- ⁇ , lL-1 ⁇ and GM-CSF /17-19/ that is independent on the virus entry /20/.
- TNF- ⁇ activation par env gpt20 proteins of the secretion of cytokines: TNF- ⁇ , lL-1 ⁇ and GM-CSF /17-19/ that is independent on the virus entry /20/.
- a production of the ceramide at seropositives /21/ confirms an action of TNF- ⁇ .
- the TNF- ⁇ secretion is proportional to an appearance of le ⁇ th/irus antigens /22/.
- a secretion of this cytokine inducts an appearance of the adhesion molecules in target organs /10/, reflecting a presence of only (almost) contaminated macrophages in the corresponding organs /10/.
- the Fc receptor helps to the virus to penetrate directly into cell by means of a fusion of the viral envelope membrane with the plasma memb/a ⁇ e.
- the strong signal (as mitosis) must be essential for the real virus infection /27/.
- Fc receptors i ⁇ terferon- ⁇ (IFN- ⁇ ), macrophage (granulocyte-macrophage)-colo ⁇ y stimulation factors M(GM)-CSF/, cytomegalovirus (CMV) /28,29/. So the IFN- ⁇ without antibodies (in vitro) does not provoke an increase of the virus multiplication /30/.
- the CSFs make it through an influence on the IFN- ⁇ respone region of the FcR (receptor Fc) gene promoter /31/ or through an increase of a quantity of the cells with Fc ⁇ R( I I I ) receptor /32/.
- the CMV has no effect at the 1st step but has it at the 2nd step (AIDS) where it decreases significantly a time of survival /33,34/, being the cause of the serious morbidity in the advanced HIV infection /35/.
- a quantity of cytokines during this 2nd step is well elevated /36.11/.
- the Fc receptor activation induces the Fas ligand synthesis /37/.
- the Fas receptor-Fas ligand complex can produce a complementary signal, stimulating a producton of IL-2 interleukine (important at last stages of B-T cells interactions- Fig.1 ), TNF- ⁇ , IFN- ⁇ /38,39/ in cooperation with TCR (T-cell receptor) /38/ (it means: with CD4) /40/.
- the FcR induces the cytokine synthesis (as TNF- ⁇ or IL-1 ), that activates the complete /4/ signal machinery /41-44/, according to the activated elements /17/.
- the TNF- ⁇ induces the HIV production through the activated NF-kB (by transcription), making also the new TNF- ⁇ /42,45/.
- CD4 glycoprotein An interaction between the CD4 molecule and viral envelope proteins are multimolecular /46/ that permits to make the stonger conformational change of CD4 /47/.
- the CD4 glycoprotein must have a special conformation enable it to interact with glycosphingolipids and phospholipids in creating the receptor signalling complex (sometimes with dimerisation for small
- the IgG is also the switching part of the membranous Fc receptors and receptors for antigen of the B cells, one can predict a 0 presence of such little fundamental protein for Fc receptors (and receptors for antigen of B-cells) 13/ and also for receptors CD4- like ( in above sense) and other receptors of lg family like ICAM-1 (intercellular adhesion molecule) also having the hinge region between two globular parts, each one relatively rigid with close S-S bond /56/.
- the fundamental proofs of Universality (by Universality!) of such general very important mechanism is given below (Parts VE-X). Consequently, an interaction with protein env of HIV switches the discrete state of
- CP4 (as well of env viral proteins )(proved definitively in Parts VE-X), that permits, justly, to interact with glycolipids with help of the homologous intercarbohydrate interactions /4/ in making the complexes: glycoreceptor ⁇ gangliosides ⁇ cerebrosides ⁇ ⁇ sphingomyelin ⁇ cholesterol ⁇ ... with phase separations /4/.
- Such complexes make some aggregations with unification of the same phases.
- Cytokine receptors are responsible for 1st entry of HIV viruses into the monocytes/macrophages during their movement. There is a number of cytokines ( ⁇ ) that attracts the monocytes having the corresponding high affinity receptors /63-68/, participating in the macrophage recruitment within tissues /66/. These chemokines are released by the infected (HIV) macrophages /66,67/ or by immunocompetent cells as Nuclear Killer (NK) or T8 cells after a release of the special cytokines (as TNF- ⁇ or IL-l ⁇ ) by the monocytes after an injection /68,69/.
- HIV infected
- NK Nuclear Killer
- T8 cells a release of the special cytokines (as TNF- ⁇ or IL-l ⁇ ) by the monocytes after an injection /68,69/.
- ⁇ -cytokine receptors also can activate cells /66/, whereas in the T4 cell case (in vitro) and the monocytes/macrophages, they coinfect these cells with HIV /64,65/.. But in the case of the inactive ⁇ -chemokine receptor (CCR5-2 alleie) there is no appearance of the anti-HIV seropositivity in vivo (and, evidently hi, AIDS) /65/ that means (together with an absence of the HIV virus infection in such cells /65/) the virus entry absence in macrophages in vivo at the 1st stage where the CCR5 receptor was responsible for the HIV entry /see also 64/.
- CCR5-2 alleie inactive ⁇ -chemokine receptor
- the 2nd state (so called "scrapie") of prione protein (also more rigid!) is created justly because of the dissociation of Du-2T like proteins during signalling (Part X) with consecutive homologous intercarbohydrate interactions with bond crosslinkings during the signalling in the zone of principal receptors 14/.
- the same signalling is after translocation of the specific peptide for T-cell receptor (TCR) from its not very specific complex with MHC class I (Part IX), where exceptionally, there is a presence of destabilizing charges in the hydrophobic intramembranous part of TCR /71/.
- TCR T-cell receptor
- Part IX MHC class I
- the anti-D3 domain antibodies stop the CD4 molecule signalling (with gpl20) /74/ and the D2 domain is also important for HIV infectivity /75/ because of direct interaction between D2 and D3 domains (as direct Fab-Fc interactions with Du-2T dissociation /3/) during the bending confirming clearly the IgG "scorpion" structure during antigen binding /3/.
- the similar nearby presence of 2 prolines and 2 N-chain potential sites at D3 regions of ICAM-1 /76/ and the presence of the bent of 90° between D2 and D3 domains /77/ confirm above data.
- the absolutely certain proof of such SPECIAL protein functionings was possible only due to profoud UNIVERSAL laws of protein foldings resolved by me (Parts VE-X).
- the NKR-P1 receptor belongs to the family of the Ca dependent animal lectins (C-type) with carbohydrate recognition domains (CRD) /2/.
- C-type Ca dependent animal lectins
- C- type lectins A presence of the O- linked chains at the muci ⁇ - like counter-receptors of the selectins (C- type lectins) is established /3/.
- the NKR-P1 (even without its classical N- chains) interacts with different carbohydrates, especially with ones containing galactose-N-acetylam ' me (GalNAc) (gangliosides) and glycosamin ⁇ giycans (GAG) /9/.
- the GalNAc is justly essential component of O- chains, and a presence of the GAG chains is also very natural in NKR-P1 because of their established presence at C- type lectins /2/.
- NKR-P1 bacteria
- a synthesis of N and O- oligosaccharide chains including GalNAc
- a synthesis of GAG chains also takes place /12/.
- CD43 ⁇ 1 ⁇ 6N-acetylglucosami ⁇ otra ⁇ sf erase
- CD45 /27/ and justly a branch of core 2 O-glyca ⁇ s could be long due to p ⁇ ly-N- acetyllactosaminyt /28/.
- NK and target cell glycoproteins Interactions between NK and target cell glycoproteins are species specific /37/ as well cell specific /38/. This well coincides with "strange" dissapearing of NK1.1. specific determinant of mice NKR-P1 receptor after mouse receptor gene expression in other species as well justly in genetically different mice strains /39/.
- each NK- cell type from a large complex pattern searches the target cells with the similar "foreign" carbohydrate pattern (including justly very different cancerous carbohydrate pattern /38/) on the cell surface.
- the target cell is lysed 19,371 due to, firstly, the melting of the plasma membrane with help of the carbohydrate homologous interactions hi and then the activated NK- cells undergo a proliferation /37/.
- NK- cell lysis activity against the env proteins and its absence in the case of the gag proteins or reverse tra ⁇ scriptase confirms a presence of the env glycoproteins on the cell surface /40-43/ /this activity can be also due to specific antibodies at special Fc receptor- (CD16) but it must happen later /44/, after already appearance of these antibodies/. If to make the cell synthesis of the mutant env proteins without carbohydrates, the env is absent on the cell surface and there is no NK specific anti-env answer but the CTL answer /45/.
- This fusion can be influenced by the pattern of viral envelope glycosylation" ' /48/ and infection conditions suppose very high concentrations of gpl20.
- a role of carbohydrates in an interaction between gpl20 and CD4 was already proposed /49/.
- a structure of the N- li ⁇ ked carbohydrate chains of CD4 and gp120 is similar /50,51/. Even a loss of a single glycosylation site of HIV-2 diminishes its binding to CD4 at least 50-fold /52/.
- a pattern of carbohydrates and infectivity depend on a type of host cell /38/ and particularly, there is a presence of the chains with lactosami ⁇ oglycans on HIV gp120 only at macrophages, the isolates from which have justly a better infectivity /53/, confirming such thesis and a predominate role of macrophages in infection hi.
- This Thr 324 is situated justly at the region of CD4 binding and justly satisfates exceptionally very well to a number of conditions of O-glycosylation for threonine /57/ and evidently an utilisation of different antibodies against different epitopes (including the O-linked oligosaccharide) can give variable results due to their different effects on a amplification of an infectivity due to the Fc receptor /48,6 ⁇ /.
- CD4- gpi20 there is, in particular, a creation of new interactions between one (of interacting) O-chains of CD4 (near hinge) and the V3 gp120 (Thr 324) /74/ with conformational change of CD4 and gpl20 /54/ with disruption of carbohydrate bonds between C2 and V3 of gp120 and similar INTRAmolecular CD4 bonds and conformational change of CD4 and env.
- the carbohydrate molecule must have amphipatic properties. It means that the conditions could be created when the close superpositions of the identic hydrophobic (which means that they contact each other because they do not interact well with water) glycopyranose rings will permit to eliminate the surrounding solvent molecules. The intramolecular H- bonds are destroyed already in water solution /78/. Evidently, the optimal best fitting structure must be created with help of mainly carbohydrate hydroxyl groups participating in strong hydrogen bonds /47/. Only chair (C1 ) conformation are normally preferred from two "chair” and six "boat” possible conformations /79/.
- the typical terminal cell membrane sugars /83/ have the normal C1 conformation (creating of selection?) with all equatorial OH substituent groups /83/ (as N-acetylglucosamine or ⁇ -sialic acid) or some flattened C1- derived conformation due to a tendency of one resting axial hydroxyl group (according to their normal C1 chair structure) to become equatorial (as ⁇ -galactose or N- acetylgalactosamine) (Fig.2).
- the divalent ions as Ca potentiate these interactions because of their capacity to dehydrate the area near the interacting surfaces /84/.
- GalNAc-tra ⁇ sferases Moreover, the site with lie must be, logically, giycosylated with important Core 2 chains that are made with help of T3- GalNAc transf erase ( ⁇ 1 ), logically, having a specific complex with other transf erases making such chains
- NAGR1 has a numberof potential sites for O-glycosylation justly with He (for Core 2 chains with GlcNAc) justly in Ca-coordinated domain (where Ca is necessary for intercarbohydrate homologous interactions) /9 ⁇ /. However one cannot exclude here the core 3 and 4 chains /97/ although, visibly, "much less abundant” /98,99/. Certainly, the data, with clearly well glycosylable in vitro site in V3 gpl20 HIV region by purified mammary T3-transferase (on large peptide) , relatively the same site, completely unglycosylable by T1 and T2 transferases, are correct, moreover with other data ( ⁇ 1 ).
- Intracellular A-particles are a clear reason of false viral presences after 1st contamination (seropositives). It is known that a number of viruses enter the cell by direct fusion and by endocytosis via coated pits /1/. in the case of the HIV virus, one can see the same double picture during artificial contamination of cells in vitro /2/ but only the direct fusion of HIV with cultured cells is sufficient for infection /3/.
- the primary Langerhans cells were "infected" by viral particles with internalization /4/.
- the viral unintegrated DNA forms exist as the multiprotein complex that is different from the preintegrated complex of HIV-1 /11/ and the viral genoms of particles, entered into questient cells (by endocytosis), are not completely transcribed /12.13/.
- Such unintegrated forms of HIV DNA in infected cells do not lead to a production of infective virions and serve as a template for viral RNA and protein synthesis /14/.
- the vif viral protein for instance, is important for the early event after virus entry resulting in reverse transcriptase activity /15/.
- the unintegrated lenti viruses DNA produces a large number of defective RNA which could be packed in "virions" without env proteins /13, 16-20/.
- the heterogeneity in vivo did not changed /17/.
- the defective gag proteins make the capsules (with RNA) that are localazed in the vacuole- like structures near endoplasmic reticulum /30,3t/ although normally, this C-type virus /32/ aggregates near the integrated in plasma membrane env proteins. Similar particles buddings in the endoplasmic reticulum lumen are obtained with vectors carrying the gag polyproteins of the lentiviruses with mutations at their N-end /22,32-35/. These capsules well resemble the noninfectious spherical intracysternal A particles (IAP) /21,35 ,36/.
- IAP noninfectious spherical intracysternal A particles
- the gag myristate for the retrovirus particle (C-type) assemblage facilitates the gag protein membrane association /40.41/ although several retroviruses as EIAV do not have the gag myristate at all /32/.
- the direct proof, that the gag interactions are first ones, is absent /32/ because it is difficult to imagine their synthesis at endoplasmic reticulum but their first interactions somewhere else, near plasma membrane (for C- type viruses) /32/. In reality, it must be the ribosomes that are transported to the plasma membrane that is known for instance, for ⁇ -acti ⁇ (plasma membrane or growth axon cone) /42-44A It is the 3'-region of mRNA that directs a localisation of ribosomes /45,46/.
- the retroviral particles are mainly situated at plasma membrane with microfilaments regions (cells without excessive gag concentrations) as the punctate pattern /47-50/ and the ribosomes make a complex with them /49.50/.
- the (uninfectious) viral particles (p24) are always present at asymptotic phase
- Intracystemal A particules are the artefacts of HIV presence in seropositives.
- the gag coated pseudoparticies /justly, intracystemal A particles (with RNA and reverse transcriptase but without env proteins) exit the ceil from the cytoplasmic vesicles and enter into other cells where the RNA can serve for a synthesis of separate HIV proteins that can be exocyted.
- a measureme ⁇ t of the p24 gag protein concentrations, the reverse transcriptase activity or polymerase chain reaction of exterior solution 765,70/ produce a sense of a presence of the infectious viral particles although in very weak concentrations. But without mitogens and rigurous conditions of waitings, the virus
- nef proteins serve: (1 ) to make the heterogenous DNA copies and also (2) to disturb the HIV particles exocytosis and asymptomatic' phase.
- the attenuated SIV virus deficiency in nef
- antiviral antibodies titre ⁇ 10 times less /77/. This antibody titre increased in time (with new immunisations), / s, 80/.
- a presence of such attenuated virus correlates, justly with absence of the immunodeficiency /78J9/ at asymptomatic phase.
- >nly one strain is found at alive (during 14 years) blood donor (free from HIV related disease) with the damaged nef gene and a much lower number of the HIV DNA copies is found at this donor and his blood recepients than normally during HIV seropositive stage /81/. So one can estimate that the nef proteins influence the DNA reverse transcriptase synthesis provoking the numerous heterologous DNA copies presence (normal course) where con- sequently a mixture of anti-env and anti-gag antibodies against corresponding (to numerous DNA copies) numerous proteins makes the immunodeficiency.
- the 1st, nef defective, SIV immunisation does not protect the infant monkey from 2nd challenge with wild clone /80/. This could happen because the infants have much more active macrophages /87/ that, exceptionally, can be contaminated productively with help of homogenous antibodies.
- a quantity of anti-nef antibodies decreases /88,89/ (although that of gag p24 increases) reflecting an absence (decrease) of the nef protein synthesis at this stage.
- nef proteins have also another action with help of their SH3-binding domain (N-part), making an association, for instance, with protein kinase- ⁇ /92/ necessary for membranous cortical cytoskeleton contractions /Zagyansky Y. retired Application FR- 95-11550 with Refs./ and, at simple special mutation in this nef domain, the SIV virus mutant (SIVpbjl4) makes the cell transformation and, consequently, an immediate virus entry, multiplications and very rapid animal death /93/. But obviously, this is not the nef function because such simple mutation had to happen in nature leading to much more effective virus action in this case.
- intracystemal A-particles (easily proteolysed) ( ⁇ 1 ) permit a more effective presentation of antigen to MHC-H molecules (it means more effective creation of antibodies) because the MHC-E presentation of endogenous secretable proteins is much more efficient than that of exogenous proteins /96/.
- endogenously synthesized membranous env proteins undergo the MHC-H restricted antigen processing only after expression on the cell surface /97/.
- anti-nef antibodies soluble protein
- anti-gag antibodies they appear essentially earlier than the anti-env membranous antibodies- the key point of the course of the HIV infections in vivo /54/.
- the condom use with only partner part was ("strangely") associated with a stronger seroconversion than no condom use /108, 109/ and the borrower of injecting equipment most frequently appeared to have the lowest progression rate /110/.
- the confirmation of the general basis of complex HIV action /29-Fig.l ;54/ is clear.
- the repeated HIV virus injections in macaques could create the persistent seronegativity against env although anti-gag p55 (gag precursor) were present /111/.
- the macaque FcR carbohydrate pattern (marked with Mamu-A26 allele) also must differ stronger from that of virus env, that conducts to their "protection” (in this very special kind of contaminations) /113/ ("immunity" of chimpanzees- Part iy, ⁇ 4) at justly 2nd AIDS "stage” during entry with the FcR help.
- the envelope proteins are shed into serum 725/ and they attach to eel! surfaces /26/ and inhibit a migration of mononuclear and poiynuclear lymphocytes and monocytes /27,28/ and suppress an activity of cytolytic cells /29/. So there is a registed accumulation of eosinophiies (and macrophages) in such created eruptions /7/.
- the eosinophils secrete substances like TGF- ⁇ and ⁇ /30/, absolutely necessary for neighbouring cell divisions /Zagyansky.Y. retired Application N°FR-95-11550).
- the opportunist agents includedihg herpes viruses and tubercle bacillus accelerate the death due to AIDS stage 737-41/ without real change of a spread of transition from asymptotic phase to AIDS /37-41/ (/41/- with analysis of errors of other works). It is shown that the polyclonal anti-env antibodies do not activate the complement HI but the complement (Clq!) activation by other antibodies (against opportunist antigens) can lead to attachment of this activated C1q to anti-env antibodies together with attachment of C1q itself to its special Clq receptor on the HIV attached cell that facilitates the Fc (once more! receptor mediated HIV virus entry /42/.
- Child's AIDS adapted to particular characteristics: active immune . system. mother's antibodies and change of Fc receptor carbohydrate pattern around 3 months of age.
- CD4 cell quantity of such infants can diminish in 185 times at 9th month /63/. In difference with the 1st adult contamination, the cytolytic cell accumulation is weak
- the carbohydrate pattern changes with ontogenesis including a period after birth /76,77/ where the IgG oligosaccharides are indispensable for interaction with Fc receptors /78-80/ (making important self-aggregation /81/) and where justly the macrophage Fc receptors are important for productive entry of HIV virus in vivo /6,7/. So, logically, the new carbohydrate pattern of Fc receptor of infant accords with that of HIV envelope proteins from 3-4 months and the productive AIDS course can begin ONLY from this time.
- the "strange" new seronegativity of infant from also 3 months /82/ can be well explained with intensive creation of a number of new infective viral particles that are precipitated by anti-HIV antibodies.
- the new (once more) seropositivity at ⁇ 8th month /82/ must happen due to creation of the anti-viral infant antibodies.
- a better HIV productivity in vitro of neonatal (at birth) than adult macrophages /61/ confirms a help of antibodies with Fc receptors from 3-4 months in vivo.
- the seropositives with pneumonia "strangely" have a decreased AIDS development /96,97/. And justly the Pneumonia bacteria turn of the macrophages making from them the multinuclear syncytia /98,99/.
- T e new created infectious viral particles (with some "old” ones?) contaminate (with antibodies) the T4 cells.
- lymphocytes undergo the apoptosis and this "apoptosis was tight associated with formation of syncytia" /100-102/.
- a change from the non-syncytium induced to syncytium- induced isolants correlates with AIDS progression /103/.
- Only the macrophages but not the T4-cells make the budding (in vivo!) of new viral particles to exterior /103/ and the viral particles remain preferentially in cytoplasmic vesicles of T4-cells /103, 104/, especially prived of the signal transport machinery.
- the macrophages avidly phagocytize justly cells during apoptose /101/, it means the contaminated T4-cel!s are regularly destructed. So the quantity of the contaminated T-cells, present at the moment (of death included), must be low but a number of T4 cells diminish sensibly /106/ although it makes a time ( ⁇ 7- 20 months) from 2nd contamination until death /107/ justly in accord with this mechanism (Fig.3). A contamination of some small quantity of lymphocytes at 1st stage is possible, principally, especially with the T-tropic variants /108/.
- chemokine lymphocyte CXCR4 receptors with their natural ligands (SDF-1 ) slows the progression of AIDS and "blocks the virus entering the T-cells" /109/ blocking the syncytium creation (Fig.3).
- the vaccines against HIV without native nef proteins eliminate a creation of the heterogenous viral (and antiviral) population at 1st stage with general impossibility of the stable 2nd AIDS stage that takes place only with heterogenous antibodies 12.1. But with challenge of the wild virus there is only some delay /due to homogenous (only precipitating) anti-env antibodies/ for heterogenous
- the antibodies against inactivated virus or its env proteins must be more homogenous although passages of virus (taken from sick patient or animal) through the unnatural cell cultures must make such virus more heterogenous /10/ (with unpredictable degree) and these antibodies make a delay of 1 st stage entry of challenge homologous virus /9,11 ,12/ that must depend on conditions of a production of the virus for immunization. As result of such (however) entry, the heterogenous antibody production takes place (after heterogenous viral proteins synthesis) /2/.
- these yet homologous antibodies can, however, make some visible restricted sporadical entries into cell with help of Fc receptors /1 ,3/ that one can see, for instance, in clear variations of CD4 cell counts in seropositive phase in some cases 79,13/.
- Fc receptors /1 ,3/ help of Fc receptors /1 ,3/ that one can see, for instance, in clear variations of CD4 cell counts in seropositive phase in some cases 79,13/.
- the immune response after SIV vaccination does not correlate with protection /14/.
- Such, even sporadic, productive entry with help of the vaccine produced homologous antibodies already proves the clearly definitive unperspectivity of such vaccines.
- the heterogenous antibodies appear before the native virus elimination (in such interplays), the AIDS stage takes place /7-Fig.1,11-Fig.1/.
- a potential subunit (env) vaccine to enhance the AIDS disease /12/ can be due to high concentration of antiglycoprotein antibodies and their some heterogeneity due to passages of original virus through culture (see also /15.16/) where such massive presence of some heterogenous anti-env antibodies helps for (at once) productive virus entry at 2nd stage as well for increased polyclonal production of anti-HIV heterogenous antibodies of 1st stage 71 ,37.
- T cells with help of charged antibodies against active site of such antibodies /1/.
- the high,, unnatural, virus concentrations are used where as result there are the two types of viral entry: (1 ) by endocytosis and (2) by direct fusion /3/.
- the virus endocytosis characterizes sufficiently strong concentrations where the patches of only VIRAL exterior molecules can induce the endocytosis /25/ with nonproductive contamination hi.
- the created aggregates of virus particles /26/, attached near the cell surface must create a great number of interviral intercarbohydrate homologous bonds with the powerful local dehydration and membrane destabilization /3/ for direct fusion, as in the case of the syncytium creation or the cell-cell fusion with a help of viruses or polyols. So "the syncytium formation is often the first sign of HIV infection in culture” /27/. And there is a total (in difference to small "problematic" quantities of the found artefacts /28- 30/) infection of cell as fibroblasts that is not found in vivo /28-31/ and the CD4 receptor does not participate in such global artificial infections /32-34/.
- the good HIV particle production in vitro in the case of newborns which cannot take place in vivo at this time /86/ the good HIV particle production in vitro in the case of chimpanzees cells with an absence of such production for the AIDS stage in chimpanzees in vivo /3/ and an absence of an influence of the nef-mutation in vitro whereas such mutations clearly eliminate the productive AIDS contamination in vivo 73/ prove once more that a mechanism of viral contamination in cell culture is quite different and cannot be directly used for AIDS mechanism interpretation in vivo
- CMV and EBV viruses have a number of properties that resemble these of HIV virus in particular and lentiviruses in general. It was already shown that CMV and EBV viruses also have the acute and latent phase with help of heterogenous antibodies against the synthesized viral proteins (that could be included in pseudoparticles) ( ⁇ 2) that can also provoke the immunosuppression /42/. At also 2nd phase with new contaminations, in a presence of anti-viral (env) antibodies there is the more effective entry of herpes viruses with more severe recurrent diseases /43-45/ ( ⁇ 2) although (in difference with HIV) there is no integration of DNA in such cases. Logically, the severity of above recurrent diseases must be again amplified with signalings as, for instance, that appeared during transplantation /43,46/. But such integration can happen spontaneously /47,48/ or with
- GCR chemotactic receptors /49-51/ where such receptors could be situated even in enveloped viral particles /51/. So the migration increases at contaminated cells /52/ (and also through the own classical cytokines as IFN- ⁇ , TNF- ⁇ , IL-1 /53/ ).
- a number of other ⁇ -herpesviruses makes also the homologous of the chemokines /50/ that evidently alsor serves for a stimulation of the directed cell movement /60/ facilitating the virus entry by endocytosis with the consequent latent state as the obligatory stage for each herpesvirus /61/.
- the ⁇ -herpesvi ruses also stably produce such homologues /50/.
- the EBV Epstein-Barr virus upregulates the expression of the two ⁇ -chemokine cell receptors in B- cells but not in T- cells /62/ and, justly, the B- cells (naturally by endocytosis at requests) but not the T-cells are contaminated /85,p.2345/.
- the IFN- ⁇ and IL-i ⁇ increases strongly during such phase /65/ and IFN- ⁇ inhibits the capping /64/.
- Such produced chemokine receptors are justly absent at all ⁇ -herpesviruses /50/ and, for example, the 1st entry of HSV (human simplex virus) must take place differently, by direct fusion /66/, that justly cannot be done during the well synchronized cell motility but after the direct attachment to corresponding cell surface receptors.
- HSV human simplex virus
- the viral envelope glycoprotein reacts with Universally present heparin sulfate proteoglycan (HSPG) molecules /73,74/ (potentially with syndecan /75/) with oligomerization /73/, and the particular gangliosides are also necessary for HSV action /76/.
- HSPG Universally present heparin sulfate proteoglycan
- a number of microfilaments must attach to such massive syndecan aggregates /3/ making disequilibrium and as result, the signals as the spreading and migration are inhibited in contaminated epithelial cells /77/.
- a reactivation of the latent HSV infection in neurons can be done after neuroctomy /78/ which activates well the signal machinery axonal transports.
- Flaviviruses dengue, yellow fever, Japanese encephalitis, langat encephalitis, St Louis encephalitis
- Coronaviruses feline infectous peritonitis virus
- Orthomyxovi ruses influenza A
- Lactate dehydrogenase elevating virus and related viruses PRRSV virus
- Parvoviruses aleutian mink disease parvovirus
- Paramyxovi ruses respiratory syncytial virus
- Togaviruses venezuelian equine encephalitis
- Picornavi ruses foot-and-mouse disease virus
- a number of fundamental definitive confirmations can be done even during very short time: (1 ) easy clarification of a presence of IAP (intracystemal A-particles) in real seropositives after their creation /2/ but not of the HIV infectious viral particles: end of a myth of sleaping lentivirus; (2) creation of conditions of real AIDS development in vitro: a)1st contamination: chemokine and cytokine concentration gradients for macrophage movement with corresponding (to in vivo) substrates, b) 2nd contamination:
- the . encephalites produced by a number of viruses (like HIV virus- Part.l, ⁇ l ), have place due, at the end, the movement, of the macrophages into the brain, conducted by concentration gradient of ⁇ -chemokiries (Part. I , ⁇ 1 ,4). Consequently, in perturbing the movement of the macrophages (for instance, with antibodies against chemokine receptors), one prevents the encephalites, provoked by different viruses as CMV, for instance.
- titers of the viruses, determined in vitro are false (Part.V, ⁇ 2).
- the conditions for determinations of the virus titers must be the most close to ones in vivo.
- the HIV envelope proteins switch the complete signal to enter the cell /Parts I ,V;Refs.57- Part VD7 including the creation on the cell surface of the network of the very essential hydrogen bonds (including those between env and CD4 carbohydrates) which can be destroyed (from outside) by the strong charges, locally introduced with help of the antibodies (lectins), directed against the env proteins, thus preventing the virus action. So one can make such effective antiviral preparations also against different viruses and also other parasites as the bacteria or machrooms, in making the charged antibodies against the molecules of their surface cutting their life (signallings).
- the chaperons represent members of structurally unrelated protein families that interact specifically with newly synthesized (nascent) proteins and prepare them for their normal functioning. But how all these synthesized proteins with so different structures can be recognized by very limited quantity of structures (where, for instance, a quantity of antibodies active sites is enormous!? Obviously, the Universal modifications of proteins must be specific for such specific recognitions.
- the glycochains are the best candidates. With help of very specific intercarbohydrate interactions, based on the important law of homologous intercarbohydrate interactions (Part H, ⁇ 3), one must wait the natural solution.
- the aggregation of proteins justly must take place due to the homologous interactions of their carbohydrate chains, like with IgG (Part VI).
- ER folding There are two principal pathways of protein foldings: through endoplasmic reticulum (ER) ⁇ Golgi and in cytoplasm.
- the ER folding begins from the growing . nascent polypeptide chain which is modified generally cotranslationally with N- linked sugars /13/.
- the monoglucose site is the very special motif: C-X-S-X-P-C /19.20/ and, very specially, there is the very similar invariant motif (C- X-S-X-P-G-C) in the calnexin, justly /21 ,22/!
- the calreticulin (primary Ca binding protein) is also attached (at the same time) to the calnexin complex with the polypeptide with the monoglycosylated N-chain /17.18/ although it has no such potential site /21/.
- the obvious complex between the calreticulin and calnexin 23/ shows the possibility of such complexation.
- the similar structures between the calnexin and calreticulin /19/ can guarantee the homologous intercarbohydrate interactions between their O-chains, revealed due to the potential O-sites /24/.
- the other important ER chaperon is the BiP/grp78 (Hsp 70 family), that binds soon after the chain translation into ER /15, 16,26,27/. It has many potential O-glycosylation sites justly in the substrate binding domain (and has no N- and GAG- /28/ potential glycosylation sites) /29/. So it could be specialized for the O-chains (with homologous intercarbohydrate interaction help). And justly only the BiP accompanies the new synthesized proteins during their established recycling circuit ER ⁇ Golgi ⁇ back to ER /30/. And justly only during this path, they could be O-glycosylated in Golgi /31/. The accord of the mutual interactions with the chain associations of the BiP chaperon and IgG chains with their potential O-glycosylation sites confirms such thesis (Part VI, ⁇ 3).
- the definitive chain creation must take place with the gp96/GRP94 chaperon (similar to Hsp90 in HSP90 family /15,36/), serving (in analogy with Hsp90 in cytoplasm /Part VI, ⁇ 2/) as the framework for the large agglomeration with the other chaperons: mainly BiP, calreticulin, p50-like protein, Peptidyl-prolyl isomerase (PPI) and Protein disulfide isomerase (PDI) /23, Part VI, ⁇ 2/.
- the gp96/GRP94 chaperon similar to Hsp90 in HSP90 family /15,36/
- the other chaperons mainly BiP, calreticulin, p50-like protein, Peptidyl-prolyl isomerase (PPI) and Protein disulfide isomerase (PDI) /23, Part VI, ⁇ 2/.
- the proteins, having the potential GAG binding sites exist in ER.
- the PDI has the heterogenous population with the conformational changes with ATP /24/, reflecting the PDI family presence /42/.
- the PDI has the strong invariant GAG potential sites (heparan sulfate) /43,28/, including the yeast PDI (Eugl protein) /44/.
- the other members of the PDI family do not have such sites, reflecting the functional complexity: folding and disulfide isomease (as such) activities /46/: Erp72 /43/, P5 (phosphatase) /47/, including the yeast PDI (PPI-1 ) /48/!
- the PDI ERp61 family protein does not belong to the ER proteins. It does not have the ER carboxyl-terminal retention signal (but QEDL) /49/. "Erp61 did not rescue the PDI1 deficiency" in yeast as the other mammalian protein disulfide isomerase related proteins /49/.
- the activity presence (attributed to ERp61 ) is very ambigous and variable according the results, obtained with the recombinant proteins /50/ /often with very different evolutionary cell origin that could be the very important error (Annex of Part I)/ and even measurement conditions of the PDI activity always do not correspond to those in vivo (with peptidyl-prolyl isomerase) and "obviously, we do not know” "what does PDI do in vivo" 751 , Part VI, ⁇ 3/.
- the ERp61 mRNA tissue distribution is very different from 2 other ER PDI family members /52/.
- this ERp61 (grp58) protein is clearly the active cytosolic phosphatidylinsitol- specific Phospholipase C ⁇ /53,54/ and it is only its resting (after N-end proteolysis) part that is active /53,54/ (moreover there is only 1 contradicting work in vivo in situ).
- the clear (almost) absence of PI-PLC activity at ER (logically, yet ribosome attached chains can go inside even after synthesis /56/) or a contamination of, even transfected with Erp61 , mammalian cells (less than 0.1% in cytosol of other type control cells) confirms location (on "PKC" transport vesicles /57/) of this PI-PLC- ⁇ .
- the GPI- transamidase is localized in ER 761/ and logically attaches the GPI after proteolysis in Golgi with help of the COOH peptide, logically making suitable conformation for GPI anchoring. Due to a presence of the ceramide (contained in the GPI ), the GPI- attached protein clusters go with glycolipids (also ceramide based) /57/ in trans-Golgi and later to plasma membrane (PM) without dependence on glycosylation /62/. It is interesting that the GPI with both types of lipid moiety contains the long 26:0 fatty acid /63,64/.
- the PDI is identical to the glycosylation site binding protein /48/ and universally binds to the giycosylated universal peptides /51/, logically with O- glycochains (according to numerous potential sites /48/).
- the folding is finely regulated by PPI, having numerous genes /66/.
- the S-S bonds help to make the functional proteins and after reduction of the S-S bonds there is an increased synthesis of Hsp and Grp proteins (feedback) /68/.
- a precise function of these two enzymes remained obscure /69J0/ because the mechanism of functioning of the protein folding was unknown (Part VI, ⁇ 2, 3). ⁇ 2.Cytoplasmic chaperon machinery.
- the cytoplasm folding is analogous to ER one although the cellular agglomeration happens on the ribosome (or ribonuclear particle- RNP): even O- glycosylation (GlnNAc) takes place on the polypeptides, yet attached to ribosome (in cytoplasm) /71-73/. Consequently, the Hsp70 (family) attaches with TRiC (chaperonin family) to elongating polypeptide /15, 16,74/.
- the Hsp70 must be specialized to the O- chains according to its numerous potential O-sites /29/ and the TRiC justly has numerous special potential O-sites with He /75/, that must induct (although in Golgi synthesis) the special long core 2 chains (Part I). So the specialisations are also well traced.
- the cytoplasmic glycosylations are some specific although the Rules are some similar to those in Golgi (Part I): nearby positive amino acids, proline and closeness of at least 2 Thr and/or Ser residues. Normally, reflecting their homologous intercarbohydrate interactions, these proteins with such glycosylation are mostly multimeric associations /76/.
- TRiC and Hsp70 are the ATPases /16/. Consequently, the principal complex with
- Hsp90 as an essential component, is formed /76/.
- Hsp90 is fundamental to biology of the eucaryotic cell" /76/.
- This complex, serving for folding (Part VI, ⁇ 3) is analogous to definitive complex in ER (after circuit from Golgi) (Part VI, ⁇ 1 ) and there is no, already, TriC (chaperonin) in this complex /76/.
- the Hsp90 (“ship") (having heparinase- like domain- Part VI, ⁇ 1 ) makes the complexes with p50 /76/, that is homologous to GAG binding protein /77/ and justly has the invariant GAG potential binding sites /77/.
- the p50 (equal to important cdc37 /78/) binds to GAG even in vitro and there is an antibody, specific justly for protein site, responsible for GAG binding (near GAG potential site: DSG) /79/.
- the splicing p50 form without such potential site does not have such binding of the specific antibodies (it means GAG binding) /79/.
- the cdk4 molecule which bind specifically the cdk37 (p50), justly, has the strong potential GAG binding site /80/.
- each of these proteins goes to the constructing in nucleus preproribosome, naturally recognizing its "ship” complex and later they return into the cytoplasm with their proribosomes and wait only the activation signal (Annex AI ,AI).
- Annex AI activation signal
- aH steroid receptors proprotein forms wait the signal in complex with hsp90 (and other attached to it molecules) that binds and neutralize the steroid binding domain /76, Annex Al , Al/.
- the phosphorylation by CK-I protects these molecules against proteolysis (Annex Al ) and an activation of the phosphatase after action of steroid hormone.
- PP5 The inhibition of PP5, justly, leads to the permanent protection of complexes of steroid receptors with their presence in cytoplasm /87,84/.
- the limited proteolysis of PP5 (having also the GR sequence at C-end /88/) conducts to its activation /89/.
- the PDI can be involved in the cleaved propeptide (Du-2T-
- the complexes with FKBP are found in nucleus 776,84,86/ and there is only a undeterminated quantity of CyP-40 molecules that are in complex with steroid ("GR"- like /Annex AI .AI/) receptors /76,86/.
- GR steroid- like /Annex AI .AI/
- the necessary (for the stocking complex activation) PP5 is justly the FK506 binding protein /84/.
- CyP molecules which were found, justly, clearly only in cytoplasm /90/, logically, must characterize the complex that folds the "purely" cytoplasmic proteins without GR peptides and without “trips” in nucleus. The folding of these proteins is ustly, different (VI, ⁇ 3).
- the above results help to resolve the very important, yet unknown, mechanism of the protein foldings (at least 3 types).
- the foldings take place with help of PPI where the 2 coupled prolines are. transformed from trans- to cis- state /68, 66/.
- the two S-S bonds are not absolutely required to maintain the protein in folded conformation /66.91/.
- the apolipoprotein A-I without cystein residues is maturated in ER with (logical) cleavage of peptide in Golgi /99/.
- signaling "PKC” vesicle transporting molecules having the GR peptides and making the "trip" in nucleus /Annex Al , 57/ and "pure” cytoplasmic molecules.
- the classical example of molecules with "GR” peptides is steroid receptors (Annex AI .AI). Their folding must take place oh the ribosomes in cytoplasm with help of hsp90 "ship” machinery (Part VI, ⁇ 2).
- the neutralization of hsp90 action during folding leads to loss of the steroid binding activity at all /10O/, it means there was no folding with PPI activity.
- the new assembling of the chaperons with receptors in nucleus in constructing preproribosomes supports the hormone receptor activation state in cytoplasm where the constructed specialized proribosome with proteins (RNP) goes in cytoplasm and waits the activating signal /Annex AI .A , 57/.
- the case of folding of "pure" cytoplasmic proteins, representing many enzymes, is quite interesting.
- the cytoplasmic synthesized enzyme rhodanese (developed case) that goes to mitochondrium, has a number of potential O-sites and a number of prolines
- the N-segment in chain is necessary for folding (evidently with PPI) and this folding is necessary for enzymatic activity /105/.
- the proteolysed N-segment associates with whole molecules, although the whole molecules (folded already!) have an activity independently on presence of cleaved peptide on it /93/.
- the N-end attached peptide (“Du-2T") (as in the case of ER ⁇ Golgi secreted proteins) must be hidden with help of homologous carbohydrate chains and it is important for enzyme targeting and translocation /93/.
- Con-2T N-end attached peptide
- the immunoglobulin G (IgG) (even as antibody) behave as classical prione aggregates ⁇ that must mean that a number of IgG. provokes other ones in common aggregates), in loosing real Little Protein Du-2T (mol.w. ⁇ 1500 /1 ,2/). At a loss of such immunoglobulin G (IgG) (even as antibody) behave as classical prione aggregates ⁇ that must mean that a number of IgG. provokes other ones in common aggregates), in loosing real Little Protein Du-2T (mol.w. ⁇ 1500 /1 ,2/). At a loss of such
- Du-2T protein the IgG conformation, justly, become more rigid /2/.
- This Du-2T protein logically, is originated from the proprotein sequence, beginning from stop codon /Annex
- the chaperon BiP binds each heavy chain with their consequent aggregation at Fc part but not at Fab part. At the same time, the BiP binds to each light chain. The interchain V domain s-S bonds are formed before BiP dissociation
- MBP mannose binding protein
- MHC major compatibility complex
- MHC class I molecules are not the total exception for chaperons.
- the ER ⁇ Golgi transported proteins the MHC class I heavy and light chains are contranslationally translocated into ER and are classically giycosylated and make the native heterodimer with help of different chaperons (Part VI) as calnexin and BiP /1/.
- the C ⁇ domain is more disordered and its folding is unsymmetrical to the C ⁇ domain /4/ that clearly must facilitate the Du-2T- like peptide dissociation (protected logically by symmetrical N-chains nearby the S-S bond /13,14/) (Part VI, I), leading to strong conformational changes of TCR ⁇ , ⁇ chains /4/.
- the TCR ⁇ -homodimer cannot be active with MHC /15.16/.
- Such conformational changes of TCR must permit the more intensive intercarbohydrate interactions between O-chains of the ⁇ i and ⁇ 2 domains of MHC and TCR in increasing general affinity.
- the MHC glycochains and monosaccharide pattern inhibit specifically the allospecific cytotoxic cells /19c,19d/.
- Such carbohydrate allotype pattern determines the inherent TCR repertoire presence (specific for MHC) /20/.
- the cytotoxic T lymphocyte polyclonal answer activation (without MHC presentation) directly by the attached (to cell) carbohydrates, and a stronger answer for the carbohydrate part of the peptide /21-23/ can be explained by the rigid carbohydrate determinants and the evolutive presence of a large number of the TCR and MHC active sites against such concrete important determined structures. So, even solely, such carbohydrate origin of specificities of the alieles, proves the Law of Homologous Intercarbohydrate Interactions.
- the peptide for 03 MHC I domain must be also made from the propeptide with help of the proprotein convertases, responsabl for the endoproteolytic processing of the proproteins, like furin, concentrated in trans- Golgi network (Part VI). But in the ⁇ 3 region of MHC, the dissociation of its "Du-2T” must be due to direct dissociation of the covering interacting carbohydrate chains (Part VI, VI). There is no prolines in ⁇ 2 domain for Ig— like signal transduction from "active ⁇ i ⁇ 2 site” /5,6/.
- the ⁇ 2-microglobulin having many atomic contacts with underside of the floor and with conceived ⁇ 3 domain /2/ and having many concerved carbohydrates /28/, dissociates from heavy chain after peptide "dissociation" /2/.
- MHC class I molecules synthesized in the same cell /4-6/, which cannot represent the numerous types. So the MHC class I- ⁇ 2 heterodimers wait the corresponding peptide in ER /29.30/ from gp96 or prolyl isomerase or calreticulin (Part VI) to have a possibility to leave the ER and Golgi for plasma membrane.
- Part VI prolyl isomerase or calreticulin
- TCR receptors ⁇ 180 par one ligand!
- Part X the numerous dissociations and associations of the affine TCR-MHC-peptide complexes are far from reality. For instance, the strong conformational changes of the MHC chains already take place after "1st" (and last!) interaction with TCR /2,4/ and already this new state triggers the creation of the complexes of TCR- ⁇ with CD8, CD3, CD45 (CD4) /33-35/.
- Cow and Creutzfeldt diseases is the ARTIFICIAL dissociation of "Du-2T" peptides.
- PrP ER ⁇ Golgi /glycosylphosphatidylinositol (GPI)-anchored/ proteins /1-4/.
- the PrP certainly has general characteristics of such folded proteins: the 2 nearby prolines, the S-S bond, important for general conformation, the 2 nearby N-glycosylation sites /1 ,3,5/ and they are made and folded with help of the corresponding chaperons /Part VI, 6/.
- PrP is soluble in various detergents but the cross-linked PrC forms the soluble aggregates /17/.
- Levels of the PrP mRNA are developmental ly regulated /17/.
- there is the decrease of the signal with the decrease of concentrations of cellular isoform at scrapie /18.19/ and the synthetic prione protein fragments (without corresponding carbohydrates) are toxic but those from natural sources (with corresponding cross-linking carbohydrate chains) increase the signaling /20/.
- the folded form with small Du-2T- like protein is easier proteolysed /2, 21 , 8, 17/ and has the same amino acid sequence /2,8/ and, even, does not differ at level Of the posttranslational chemical modification /22/.
- the "DU-2T” 1 must be hidden bythe nearby interacting homologous N-chains and consequently there is the species specificity (the same sequences) of the cell free prione conversion /8,23/.
- the point mutations naturally and exprerimental
- PrP /1/ The aggregated scrapie form destabilizes easier the cellular prione form /1 ,2/ in reacting with their carbohydrate chains and in provoking a dissociation of the Du-2T-
- the region of "Du-2T" protein in exon 2 (cleavage of C-region is not known here) is the area of the highest homology /25/ and the fused N-end of yeast prione does not produce the N-peptide, necessary for folding (Annex Al, Part VI): no folding- no prione- like properties /26/.
- the incubation scrapie time is often shorter /8,27,28/ that could be connected with perturbation of the important propeptide sequence.
- ANNEX. A I Universal Signal Transduction from Plasma Membrane to Nucleus: pH Increase ⁇ lncreased Cathepsin L (CL) Synthesis ⁇ Liberation of Stocked on Ribosomes
- Reticulum ("calcisomes") to respond for cellular organism needs /1/.
- ER Reticulum
- Such known vectorial transport during the cell movement or the axon cone growth is only particular case of my general conception.
- the Na + /H exchanger presents in all eucaryotic cells where it makes the pH elevation after many different signals /7,8/. This pH elevation can be switched. after activation of the special forms of the PKC /8-10/. Such elevated pH is present during hours (even after simple phorbol application) /9/. Only stable increase of the exterior pH is sufficient to provoke a more intensive cell growth with 2-4 times higher density /11/ and logically, the simple diffusion of the small H (and small Na ) ions through the cytoplasm must reflect such changes (Fig.4). But the increased interior . pH stimulated a more intensive protein synthesis as was shown for many cell types
- proteins participating in the mRNA biogenesis have the special motif structures ( ⁇ -sheets and ⁇ -helices) for RNA binding /18.19/.
- the ribosomal proteins have the special arginine rich (methylated) motives (ARM) (particularly, IN THE MIDDLE of their structures) for binding the rRNA hairpins /18.20/, permitting the specific interactions with rRNA.
- ARM arginine rich (methylated) motives
- this rRNA serves also for attachment of a number of other proteins in the preproribosomes (pre-ribosomal particles- rRNA and ribosomal, proteins) in nucleolus.
- preproribosomes pre-ribosomal particles- rRNA and ribosomal, proteins
- bFGF basic fibroblast growth factor
- N- methylated (asymmetric dimethylarginine- ADMA) proteins major nuclear protein- nucleolin /24/, nuclear protein- fibrillarin /25/, ribosomal protein S2 /26/, heat shock proteins /27/, actin /28,29/, visibly tubulin /29/, a number of the undetermined yet proteins that are bound with ribosomes /30.31/.
- the 2nd limited proteolysis (proribosomes ⁇ ribosomes /Part Vl/), with detachments of the ADMA rich ends of the nucleolin and fibrillarin, must take place in cytoplasm.
- the CL accounts for the main part of the cystein protease activity in the cell /38/, being the major excretion protein (MEP) that is different from any protease /39,Refs.40/.
- the mRNA and rRNA are localized together /45/, justly, at the zones of the signal action (cone growth and cell motility are only particular cases of the general complete signal IM).
- a presence of the rRNA in developing axons and dendrites /46,47/) (where the ribosomal transport with help of the axon's subcortical circumferential regions is well visible /49/), a presence of the ⁇ -actin mRNA in the growing axons /49/ and in the lamellipodium /47,50,51/, a presence of the tubulin mRNA in the growing axon cone /49/, a presence of the mRNA of GAP-43 and MAP-2 as well of mRNA of the inositol triphosphate receptor (type 1 ) in the growth cones 746,47,52/ and a presence of the ⁇ - actin mRNA near the PM after signal in fibroblasts /5
- arginine N-methyltransferases are very predominant /57/, there are evidently other highly specific protein methyltransferases /Refs.58/. But their regulation with biological purpose must be different. For instance, the carboxyl dimethylation of the protein phosphatase 2A takes place with other specific methyltransferases /59/.
- PLC transport vesicle signal exocytosis (justly unfindable pinocytosis) /1/, showing an increasing presence of the CL in cytoplasm.
- the ionophore monensin transport vesicle signal exocytosis (justly unfindable pinocytosis) /1/, showing an increasing presence of the CL in cytoplasm.
- the ionophore monensin transport vesicle signal exocytosis (justly unfindable pinocytosis) /1/, showing an increasing presence of the CL in cytoplasm.
- the ionophore monensin transport vesicle signal exocytosis (justly unfindable pinocytosis) /1/, showing an increasing presence of the CL in cytoplasm.
- the ionophore monensin transport vesicle signal exocytosis (justly unfindable pinocytosis) /1/, showing an increasing presence of the CL in cytoplasm.
- this activity increases in ⁇ 100 times /71 with
- the early appearing nuclear factors (as NF-kB, ..cHun, c-myc) conduct the signal due to their liberation in the cytoplasm by the limited CL proteolysis after a pH increase.
- the stop codon is found already at 19 or 12 or 19 amino acids upstream of the
- PLC transport vesicle machinery /1/, such dipeptide had to be sufficient for asymmetric arginine dimethylation /41/.
- IkB with Subsequent limited proteolysis /79/ by autoactivated CL (including a detachment of ail stocked proteins from ribosomes) must take place.
- the CL Activates the Ribosomes in Cytoplasm. Ribosomal Tournover.
- the above data help to clarify the complex pathway of the ribosomes.
- the CL After an initial activation of the preproribosomes in nucleus, the CL must proteolyse (in proribosomes in cytoplasm) their particular proteins at the GR peptides (that bind their corresponding sites at the preribosomes, migrated from nucleus)
- nuclear proteins are nucleolin and fibrillarin and several ribosomal proteins like L5 /Refs.90/ and several other preribosomal proteins /1 ,41/.
- nuclear proteins as the nucleolin and fibrillarin logically, served only for ribosomal partial assembly /91.92/ and later as the "fusible" and their function had to be principally accomplished after CL proteolysis that is confirmed by a difficult detection of the nucleolin pool in cytoplasm
- proteolyses must activate the proribosomes and justly, because of this ,the eucaryotic (pro)ribosmes can be activated in yitr-o only with reticulocyte lysate that must, logically, contain the activating CL.
- the proribosomes go from the nucleus into cytoplasm with help of the nucleolin and fibrillarin /93/ and of the mRNA serving as a guide (by its 3' part) for the cytoskeletal localisation (near "interior” and “exterior” "railway stations” of the "PKC” transport vesicle machinery) 71 ,41/ to work after 2nd obligatory activation in cytoplasm.
- mRNA coding nonstocked proteins
- hnRNPs /99/ heterogenous nuclear ribonuclear proteins
- a creation of the specific for each signal network of the membranous proteins is necessary mainly for a creation of the "outer" "railway station” (including the intergin's sub-station /1 , Y.Z. Application FR-95-11550 retired/) for the "PKC” vesicle transporting cycle, including the' melting of PM with help of the homologous intercarbohydrate (locally dehydrating) interactions /1 , Part I/.
- PLC transport vesicle machinery proteins with a number of functional facts in spite of a number of errors in DNA sequencing data /5/ is very convincing.
- propeptide with GR sequences in the CL molecule ⁇ 75 amino acids
- CK-I casein kinase I
- CK-I vesicular 12.1
- Cathepsin L The always present GR groups in CL determine, logically, an attachment of these molecules to the ribosomes at stocking /Refs.8-11/. Moreover, it is very visible that this GR group determines also a place of the proteolysis at the same nearby area that can be at very (!) different bonds there (Gln-Glu and Met-Leu) producing in vitro ⁇ 30 kDa single chains (from 39 kDa) /12/. But in the case of human .
- this GR group is situated the 51 amino acids downstream /Refs.8/ and consequently there is a global creation of the smaller 25 kDa mature form already after the net cell spreading (signal!) (without "processing defect” /13/ taking place due to, logically, the lysosomal digestion with, for instance Cathepsin D) .
- Such excitnig dependence of the proteolysis region on the GR peptide location is well confirmed in the case of the trematode CL (38 kDa) /10/ where the GR group is closer to C-end and consequently the size of the proteolysed form (31 kDa) justly correspond to such area.
- the position of the GR peptide is similar and much closer to the N-end and, once more, the molecular weight of the proteolysed form ., equal to 28 kDa (with 217 amino acids from 322) , corresponds to such proteolysis location (especially without posttranslational modifications de facto) /11/.
- the c-jun It is known that the nuclear factor c-jun is also bound in cytoplasm "in waiting" the signal /15/ being activated with the calpain (CL- like protease) cleavage /16/. However, it has such sequence in the N-end of the proprotein if to continue the 5'- nucleotide sequence upstream until the stop codon, always present /17, Refs.18/. But also, there are the sequences of c-jun without such GR peptides before the stop codon (at 5'- end) /18, Refs.19,20/.
- the p53 also the important regulatory protein p53 always has (25 cases!) several such groups at its C-end and never at its N-end including the sequences upstream "open reading frame" ("ORF") until the existing "5""- stop codon /Refs.2l ;22,23/.
- ORF open reading frame
- this p53 protein binds the mdm-2 protein with such N-end, making an interaction with the rRNA with its free C-end with GR peptides (including final covalent binding by its extreme amino acid to 5.8S rRNA) /24/.
- the p53 liberation takes place also with proteolysis of its C-end part in the cytoplasm.
- the c-fos protooncogene (3 cases) does not have the group GR upstream of "ORF" until "5"' stop condon (Refs.19).
- PI-PLC phosphatidylinositol- specific Phospholipase C
- the nucleolin CK-I and bFGF.
- the important nuclear protein nucleolin makes interactions by its N-domain with chromatin and justly has no these GR peptides there although it has very intensive patches of these peptides at C-end which, in this case, justly interact with preproribosomes /44/.
- the CK-I (vesicular /2/) has the two subunit types: ⁇ and ⁇ . All chains have the constant "good" GRG site in the proximal part of its N-end (although withou GR in "prepeptide” until always present stop codon) /45,46/. However, there is an intensive presence of the ⁇ -subunits without these groups in their propeptides and sequences /Refs.45;46/. The insistent limited proteolysis of the ⁇ -subunits (with strong mol.weight change) and its absence at the ⁇ -subunit during purification /Refs.47;48/ confirms these convergent data.
- the ⁇ ( ⁇ 1 ) subunits make a complex with the spread ⁇ -forms (that are without GR- groups). in an absence of the ⁇ -subunits, the ⁇ -s ⁇ bunits do not go into the nucleus
- the short mature forms of bFGF (18 kDa) have two (D)GR groups (at N°46-48 and 88-90) that normally should not be proteolysed because (exceptionally) of their special protection-by heparin /Refs.59/, similar to heparin sulfate, that should be present in the area of the bFGF synthesis /Refs.2; Refs.59/.
- the special form aFGF acidic FGF
- Steroid receptors In the case of the steroid receptor as retinoic acid receptor (RAR) there are the 3 main forms ( ⁇ , ⁇ , ⁇ ) , where there is no at all the GR peptides in the "ORF", but upstream of the "ORF” (until "5"' stop codon) there are the strong GR(P) peptides in RAR- ⁇ and there is no such peptides in the ⁇ and ⁇ forms /Refs.64/. This must reflect (as in the case of c-jun) an easiness of the ⁇ and ⁇ form liberation (short tournover) during the signal and a longer tournover of the ⁇ - form (together with the intersignal stock).
- a dominant presence of the RAR- ⁇ forms (without GR peptides) in poly(A) + mRNA family /65/ (it logically means the destination to the exterior "railway station"- Annex Al) confirms this conclusion.
- a new location of the estrogen receptor at the cone outgrowth /66/ reflects a similar situation.
- the form of this receptor is without the GR groups in "ORF" (and upstream of it) and visibly with especially long poly(A) /67/, that justly could reflect a presence of the form longer than 67 kDa (unproteolysable by CL) justly during the cancer (with intensive signals).
- the permanent activating non-negligeable means with big piece cleaved proteolysis of such important molecules as PKC, PI-PLC or steroid receptors confirms an importance of such Universal mechanism.
- the ⁇ and ⁇ actins In the case of nonmuscle actins there are the two forms ⁇ and ⁇ that are almost identical /71/. One can see a presence of the GR peptide upstream of the "ORF” until "5"' stop codon in the ⁇ and ⁇ nonmuscle actins /72 with RefsJ.
- the synthesis of the ⁇ -actin takes place in the neuron cone /73/ or near the PM /74/ (due to the long poly(A) tail) in difference with the Y -actin /71/.
- the actins have the GR group at 36-37 positions of the DNAase I binding loop /75/ that (also exceptionally) is not proteolysed (although the region is sensible) /Refs.76;77/ because they are
- the pioo does not have the GR sequence upstream of the NFkB2 "ORF” until the close stop TAA codon /80.81/.
- the RelBs have the GR peptide near the N-end of the protein structure with an unusually high number of the prolines near the arginine /82/ making them very proteolysable.
- the special character of the DNA interaction with the human RelB (“l-Rel”- “inhibitory”) (logically not yet proteolysed), due to a larger sequence upstream of the "ORF” until the stop codon /82/, confirms the limited proteolysis presence.
- the IkB- ⁇ (mol.weight 43 kDa) is easily proteolysed (logically) at the N-end where the resulting p40 form /83,84/ reflects the easily proteolysable sequence presence. These forms are present due to the complex of the three molecules where the quick proteolysis (from N-end) must take place at the unification of these molecules.
- the ⁇ 10 ⁇ (p52)/RelB/lkB- ⁇ complex specificity is also visible from following data: the IkB- ⁇ interacts weakly with RelB, the p52/RelB does not associate with IkB- ⁇ and the IkB- ⁇ affinity (A) to the different complexes represents the following relations: A(p50/Re!A)>A(p50/RelB)>A(p52/Re!B) /Refs.87/.
- such molecules often have the GC rich 5' mRNA /93,94/ potentializing more often an appearance of the arginine, glycine, alanine and proline, justly necessary for an above functioning including a facilitation of the proteolysis with the arginine and proline.
- GC- rich sequence diminishes a spead of a translation of these molecules because justly an increase of a spead of the "PKC" vesicle transporting machinery Universally leads to aU existing forms of cancer 12/. ⁇ 3.
- the mRNA as guide for its ribosomes.
- An another very important signal is the polyadenylation that directs the mRNA- ribosomes-proteins to an other compartmentalisation: growth cone of developing neurites or cell periphery /74,98,99/ during "PKC” transporting vesicle cycle.
- the synthesis of the hormone mRNA with a large poly(A) (with the signal!) /100, 101 with RefsJ with its compartmentalisation at the cone /102/ (or near the "PKC” transport vesicle PM “railway station”) illustrates this process.
- the biological sense of a synthesis of GAP-43, tubulin, ⁇ -actin already at the cone /73/ is obvious as well a more effective secretion of the hormone near already the subsurface "railway station".
- Part X Practical Consequences of Parts VI-X and Annex.
- the irresistible proofs of the mechanisms of the process of the interactions between the envelope viral molecules and CD4 receptors (and their Generalisation for All Virology), clearly done in Part VI (and also VI-X) with help of the establishment of very Universal Laws of Protein Foldings, Functionings and Recognitions, and the consecutive functioning of the Universal Du-2T- like proteins (Parts VI-X) also have led to the (also) Universal preparations against al] Viruses (and also other parasites: bacteria, protozoans, mashrooms).
- the synthesis of the functional proteins can be really done in vitro with help of the molecules as chaperons (with their precise and successive addings in dissociating the previous chaperon with, par example, acid solutions), like the peptidyl prolyl isomerase (PPI) and like protein disulfideisomerase (PDI) and also the Du-2T like proteins (Part VI).
- the peptidyl prolyl isomerase PPI
- PDI protein disulfideisomerase
- Part VI the Du-2T like proteins
- the PI-PLC- ⁇ vesicular hydrolyses (without measure) the phosphorylated derivatives of the phosphatidylinositol. Consequently, the substances cannot already arrive to the "railway".
- the neuron terminals are, justly, the most sensible because of the length of the axonal transport (with "PKC” vesicles).
- PI phosphatidylinositol
- Pl-P phosphate
- PI PI disphosphate
- the slow skeletal muscles are excited nonsynchronically (it means permanently with justly, the numerous innervations along the skeletal muscle). It means there are the bridges of the myosin heads on the actine during the muscular contraction. It is the solution (confirming the muscular contraction mechanism 71- Fig.29/) of the remarked (but not resolved) Haxley's paradox 78/.
- the following pulsations achieve the skeletic muscle contraction.
- the cardiac muscle has the similar conductivity mechanism /1 ,Fig.29/ and must also have the signal "trains" for its contraction. But there is no slow muscles in the cardiac musculature to keep the applied force. So the frequence in the pulsation "train" must be increased.
- Einstein-Bohr End New Atomic Scale Physics, Electric field: neutrinos and electrons in conversions, perpetual 30 motion, development: seisms, exstinguished volcans, created islands, Big Bang Energy
- EP-0347536 (1989). 58.J.Bi ⁇ l.Chem. 266,20337,1991. 59.EMBO J. 14,4686,1995. 60.Bio- chem.J. 316,623,1996. 61.Proc.Natl.Acad.Sci.USA 90,3973,1993. 62j.Biol.Chem. 271 ,
- Claims 1 ,2,5 C12M 1/18; C12N 1/36; C12Q 1/70; A61 K 39/12, 39/395; G01N 33/48, 33/50.
- Fig.1. The general schema of the Immunology /3,4/. There are the TWO interactions between the B and T lymphocytes. The 1st interaction takes place with the help of the T cell receptors (TCR) (without CD4 receptor) and the receptors for antigen of B cells
- the antigen (Ag) (*) (relatively large fragments of which are liberated into the solution by the macrophages "for" the 1st B-T interaction) is the bridge between the B and T cells, permitting the physical as well the localized directed chemical interactions between the lymphocytes. It is the membranous immunoglobulins that switch the signal with the flexible scorpion "tail" of the Fc fragment after the interaction with the antigen.
- the T4 cells have the conformational change and their CD4 receptors can make the interaction together with the TCR.
- the 2nd B-T meeting there is the interaction with the TCR and CD4 receptors of the T -cells with the MHC complex presented by the B cells.
- This contradiction conduct to the activation, proliferation and differentiation of the 8 cells with the immunoglobulin production.
- this phase there is the creation of the B and T cell memory. The B cell mitogens make their action only during this phase.
- the T cells After the thymus (TM) development (with remarkable symmetry), the T cells react by their TCR as well CD4 receptors with the macrophages (M ⁇ ).
- the macrophages (the different cells of the macrophage/monocyte origin like the Langerhan cells are also included in this term) make the general unic antigne endocytosis and digestion with the antigen presentation on the surface in the complex with the MHC-I.
- T cell proliferation (symmetrical to that after the 2nd B-T interaction) where the CD4 receptors loose the possibility to interact with the TCR.
- the T cell polyclonal activators act at this stage of the B-T interaction (and as one knows, they act on the T cells, justly exiting from the thymus, that clearly confirms the symmetry of this introduced schema).
- these B and T cells can take the majority of the antigen, processed by the macrophages from the solution ( ) / ⁇ /.
- the action sites of the autoantibodies that are the antibodies against the viral proteins: anti-gag pl7, anti-gp41 ("COOH” epitope), anti-gp41 ("NH "- epitope )and anti-gpl20 are also indicated.
- Fig.3. The general schema of the HIV action.
- 1st contamination there is the anti-env antibody creation.
- 2nd contamination there is already the productive contamination of the macrophages with the anti-env antibody help and also the contamination of the CD4 cells directly after initial contamination and the contamination by the macrophages.
- the apoptotic T-cell syncytium is phagocyted easier and RAPIDLY by the macrophages, diminishing the CD4 cell number by steps.
- the new contaminated macrophages contaminate the new T4 cells making the syncytium that is again phagocyted by the macrophages.
- the macrophage anergy (due to free envelope proteins) diminishes also the rate of the AIDS development.
- the 1st and 2nd contaminations are made by the macrophage tropic strains.
- the 1st contamination cannot be transmitted by parasits in difference with the 2nd one.
- the T-cell tropic strain (T4 cell produced!) is used for the massive contamination of the other T cells and the T-cell syncytium creation /105/. (M- macrophage, AB- anti-env antibodies).
- Fig.4 The process of the nuclear factor liberation after intracellular pH elevation with signal.
- A. The exchanger Na + /H + is activated permanently.
- Fig.5. The pathway of the vesicular cycle between the "calcisomes” (C) and the PM with the successive belts of the cortical microfilaments (consecutive) ("PKC" transporting vesicles).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Virology (AREA)
- Immunology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Communicable Diseases (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02718172A EP1481006A2 (en) | 2002-03-04 | 2002-03-04 | Universal antimicrobial treatment |
US10/505,353 US20050130125A1 (en) | 2002-03-04 | 2002-03-04 | End of aids for general virology, based on profound science as protein foldings: safe vaccines, universal antimicrobial means, mad cow end |
PCT/EP2002/002302 WO2002051233A2 (en) | 2002-03-04 | 2002-03-04 | Universal antimicrobial treatment |
AU2002249253A AU2002249253A1 (en) | 2002-03-04 | 2002-03-04 | Universal antimicrobial treatment |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/EP2002/002302 WO2002051233A2 (en) | 2002-03-04 | 2002-03-04 | Universal antimicrobial treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2002051233A2 true WO2002051233A2 (en) | 2002-07-04 |
WO2002051233A3 WO2002051233A3 (en) | 2002-11-14 |
Family
ID=8164796
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/002302 WO2002051233A2 (en) | 2002-03-04 | 2002-03-04 | Universal antimicrobial treatment |
Country Status (4)
Country | Link |
---|---|
US (1) | US20050130125A1 (en) |
EP (1) | EP1481006A2 (en) |
AU (1) | AU2002249253A1 (en) |
WO (1) | WO2002051233A2 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150029651A (en) * | 2012-05-25 | 2015-03-18 | 셀렉티스 | Methods for engineering allogeneic and immunosuppressive resistant t cell for immunotherapy |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8538572B2 (en) * | 2009-06-30 | 2013-09-17 | Lam Research Corporation | Methods for constructing an optimal endpoint algorithm |
US8295966B2 (en) * | 2009-06-30 | 2012-10-23 | Lam Research Corporation | Methods and apparatus to predict etch rate uniformity for qualification of a plasma chamber |
US8473089B2 (en) * | 2009-06-30 | 2013-06-25 | Lam Research Corporation | Methods and apparatus for predictive preventive maintenance of processing chambers |
US8618807B2 (en) * | 2009-06-30 | 2013-12-31 | Lam Research Corporation | Arrangement for identifying uncontrolled events at the process module level and methods thereof |
US8983631B2 (en) * | 2009-06-30 | 2015-03-17 | Lam Research Corporation | Arrangement for identifying uncontrolled events at the process module level and methods thereof |
US8271121B2 (en) * | 2009-06-30 | 2012-09-18 | Lam Research Corporation | Methods and arrangements for in-situ process monitoring and control for plasma processing tools |
WO2011109104A2 (en) * | 2010-03-03 | 2011-09-09 | The Uab Research Foundation | Molecular clone of hiv-1 |
WO2014164727A1 (en) * | 2013-03-12 | 2014-10-09 | Wisconsin Alumni Research Foundation | A method of treating fungal infection |
US10376583B2 (en) | 2013-09-30 | 2019-08-13 | Beth Israel Deaconess Medical Center, Inc. | Human immunodeficiency virus therapies utilizing N332-glycan-dependent antibodies and a reservoir activator |
WO2019226829A1 (en) | 2018-05-22 | 2019-11-28 | Beth Israel Deaconess Medical Center, Inc. | Antibody therapies for human immunodeficiency virus (hiv) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0492920A1 (en) * | 1990-12-24 | 1992-07-01 | Merck & Co. Inc. | Chimaeric influenza-HIV vaccine |
WO1997001640A2 (en) * | 1995-06-29 | 1997-01-16 | Smithkline Beecham Biologicals S.A. | Vaccines against hepatitis c |
-
2002
- 2002-03-04 AU AU2002249253A patent/AU2002249253A1/en not_active Abandoned
- 2002-03-04 EP EP02718172A patent/EP1481006A2/en not_active Ceased
- 2002-03-04 US US10/505,353 patent/US20050130125A1/en not_active Abandoned
- 2002-03-04 WO PCT/EP2002/002302 patent/WO2002051233A2/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0492920A1 (en) * | 1990-12-24 | 1992-07-01 | Merck & Co. Inc. | Chimaeric influenza-HIV vaccine |
WO1997001640A2 (en) * | 1995-06-29 | 1997-01-16 | Smithkline Beecham Biologicals S.A. | Vaccines against hepatitis c |
Non-Patent Citations (6)
Title |
---|
DUDICH I V ET AL: "RELEASE OF LOW MOLECULAR WEIGHT PROTEINS FROM THE FC FRAGMENT OF RABBIT IMMUNO GLOBULIN G INDUCED BY FORMATION OF INSOLUBLE COMPLEXES WITH ANTIGEN" MOLECULAR IMMUNOLOGY, vol. 20, no. 12, 1983, pages 1273-1276, XP001040471 ISSN: 0161-5890 cited in the application * |
FUJITA H ET AL: "STUDIES IN THE DEVELOPMENT OF JAPANESE ENCEPHALITIS VACCINE: EXPRESSION OF VIRUS ENVELOPE GLYCOPROTEIN V3 (E) GENE IN YEAST" BULLETIN OF THE WORLD HEALTH ORGANIZATION. BULLETIN DE L'ORGANISATION MONDIALE DE AL SANTE, GENEVA, CH, vol. 65, no. 3, 1987, pages 303-308, XP000993285 ISSN: 0366-4996 * |
GALMICHE MARIE C ET AL: "Neutralizing and protective antibodies directed against vaccinia virus envelope antigens" VIROLOGY, ACADEMIC PRESS,ORLANDO, US, vol. 254, no. 1, 1 February 1999 (1999-02-01), pages 71-80, XP002175485 ISSN: 0042-6822 * |
GONZALO R M ET AL: "Enhanced CD8T cell response to HIV-1 env by combined immunization with influenza and vaccinia virus recombinants" VACCINE, BUTTERWORTH SCIENTIFIC. GUILDFORD, GB, vol. 17, no. 7-8, 26 February 1999 (1999-02-26), pages 887-892, XP004154828 ISSN: 0264-410X * |
MEJILLANO MARISAN ET AL: "Regulation of apoptosis by phosphatidylinositol 4,5-bisphosphate inhibition of caspases, and caspase inactivation of phosphatidylinositol phosphate 5-kinases." JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 276, no. 3, 19 January 2001 (2001-01-19), pages 1865-1872, XP002204013 ISSN: 0021-9258 * |
RAVIPRAKASH K ET AL: "Immunogenicity of dengue virus type 1 DNA vaccines expressing truncated and full length envelope protein" VACCINE, BUTTERWORTH SCIENTIFIC. GUILDFORD, GB, vol. 18, no. 22, May 2000 (2000-05), pages 2426-2434, XP004192987 ISSN: 0264-410X * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20150029651A (en) * | 2012-05-25 | 2015-03-18 | 셀렉티스 | Methods for engineering allogeneic and immunosuppressive resistant t cell for immunotherapy |
KR102247979B1 (en) | 2012-05-25 | 2021-05-04 | 셀렉티스 | Methods for engineering allogeneic and immunosuppressive resistant t cell for immunotherapy |
Also Published As
Publication number | Publication date |
---|---|
WO2002051233A3 (en) | 2002-11-14 |
AU2002249253A1 (en) | 2002-07-08 |
US20050130125A1 (en) | 2005-06-16 |
EP1481006A2 (en) | 2004-12-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Fennie et al. | Model for intracellular folding of the human immunodeficiency virus type 1 gp120 | |
Levy | Pathogenesis of human immunodeficiency virus infection | |
Kozarsky et al. | Glycosylation and processing of the human immunodeficiency virus type 1 envelope protein | |
Berman et al. | Expression of membrane-associated and secreted variants of gp160 of human immunodeficiency virus type 1 in vitro and in continuous cell lines | |
Nara et al. | Persistent infection of chimpanzees with human immunodeficiency virus: serological responses and properties of reisolated viruses | |
Bernstein et al. | Human immunodeficiency virus type 1 envelope glycoprotein is modified by O-linked oligosaccharides | |
Cannon et al. | Structure-function studies of the human immunodeficiency virus type 1 matrix protein, p17 | |
Costa et al. | Interactions between Nef and AIP1 proliferate multivesicular bodies and facilitate egress of HIV-1 | |
West et al. | Mutations within the putative membrane-spanning domain of the simian immunodeficiency virus transmembrane glycoprotein define the minimal requirements for fusion, incorporation, and infectivity | |
US20050130125A1 (en) | End of aids for general virology, based on profound science as protein foldings: safe vaccines, universal antimicrobial means, mad cow end | |
Carrasco | Human immunodeficiency virus type 1 VPU protein affects Sindbis virus glycoprotein processing and enhances membrane permeabilization | |
US6984721B2 (en) | Immunological reagents and diagnostic methods for the detection of human immunodeficiency virus type 2 utilizing multimeric forms of the envelope proteins GP300, P200, and P90/80 | |
WO1988010267A1 (en) | Synthetic peptides related to hiv-env proteins | |
Day et al. | Complement receptor 3 mediates HIV-1 transcytosis across an intact cervical epithelial cell barrier: new insight into HIV transmission in women | |
Douvas et al. | Cross-Reactivity between Autoimmune Anti-Ul snRNP Antibodies and Neutralizing Epitopes of HIV-1 gp 120/41 | |
Miyauchi et al. | Mutations of conserved glycine residues within the membrane-spanning domain of human immunodeficiency virus type 1 gp41 can inhibit membrane fusion and incorporation of Env onto virions | |
Prévost et al. | HIV-1 envelope glycoproteins proteolytic cleavage protects infected cells from ADCC mediated by plasma from infected individuals | |
Viveros-Rogel et al. | Inhibition of HIV-1 infection in vitro by human milk sulfated glycolipids and glycosaminoglycans | |
Mitchell et al. | Inactivation of a common epitope responsible for the induction of antibody-dependent enhancement of HIV | |
Ahmad et al. | Surface expression of the HIV-1 envelope proteins in env gene-transfected CD4-positive human T cell clones: characterization and killing by an antibody-dependent cellular cytotoxic mechanism | |
Spies et al. | Alternate pathways of secretion of simian immunodeficiency virus envelope glycoproteins | |
Coffin | The virology of AIDS: 1990 | |
Becker | HIV-1 gp120 Binding to Dendritic Cell Receptors Mobilize the Virus to the Lymph Nodes, but the Induced IL-4 Synthesis by FcεRI+ Hematopoietic Cells Damages the Adaptive Immunity–a Review, Hypothesis, and Implications | |
Levy | The pathogenesis of HIV infection | |
Okamoto et al. | Enhancement of human parainfluenza virus-induced cell fusion by pradimicin, a low molecular weight mannose-binding antibiotic |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
AK | Designated states |
Kind code of ref document: A3 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2002718172 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 10505353 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 2002718172 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |
|
WWR | Wipo information: refused in national office |
Ref document number: 2002718172 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2002718172 Country of ref document: EP |