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PMC:7795856 / 1526-7528 JSONTXT

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LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
55 29-32 Gene denotes Tα1 Gene:134864
56 135-138 Gene denotes Tα1 Gene:134864
57 211-224 Gene denotes prothymosin α Gene:100506248
58 548-551 Gene denotes Tα1 Gene:134864
59 571-574 Gene denotes Tα1 Gene:134864
60 721-726 Gene denotes TLR-9 Gene:54106
61 857-860 Gene denotes Tα1 Gene:134864
62 1025-1028 Gene denotes Tα1 Gene:134864
63 1222-1225 Gene denotes Tα1 Gene:134864
64 1473-1494 Gene denotes envelope glycoprotein Gene:100616444
65 1581-1584 Gene denotes Tα1 Gene:134864
66 127-133 Species denotes humans Tax:9606
67 291-297 Chemical denotes sulfur MESH:D013455
68 1259-1270 Chemical denotes glutathione MESH:D005978
69 1272-1275 Chemical denotes GSH MESH:D005978
70 1427-1436 Chemical denotes disulfide MESH:D004220
71 90-101 Disease denotes calf thymus MESH:D048089
72 1186-1191 Disease denotes tumor MESH:D009369
73 1336-1342 Disease denotes cancer MESH:D009369
113 1625-1628 Gene denotes Tα1 Gene:134864
114 1963-1966 Gene denotes Tα1 Gene:134864
115 2174-2177 Gene denotes Tα1 Gene:134864
116 2502-2505 Gene denotes Tα1 Gene:134864
117 2556-2562 Gene denotes CTLA-4 Gene:1493
118 2635-2638 Gene denotes Tα1 Gene:20539
119 2706-2712 Gene denotes CTLA-4 Gene:12477
120 3047-3050 Gene denotes Tα1 Gene:20539
121 3208-3211 Gene denotes Tα1 Gene:20539
122 3338-3341 Gene denotes Tα1 Gene:134864
123 3392-3398 Gene denotes hIFN-α Gene:3439
124 3528-3531 Gene denotes Tα1 Gene:134864
125 2470-2478 Species denotes patients Tax:9606
126 2685-2691 Species denotes murine Tax:10090
127 3372-3377 Species denotes human Tax:9606
128 3505-3513 Species denotes patients Tax:9606
129 1814-1817 Species denotes HBV Tax:10407
130 1841-1844 Species denotes HCV Tax:11103
131 2542-2552 Chemical denotes ipilimumab MESH:D000074324
132 2594-2604 Chemical denotes ipilimumab MESH:D000074324
133 1793-1812 Disease denotes chronic hepatitis B MESH:D019694
134 1820-1839 Disease denotes chronic hepatitis C MESH:D019698
135 2028-2034 Disease denotes cancer MESH:D009369
136 2199-2210 Disease denotes cold tumors MESH:D000067390
137 2301-2307 Disease denotes tumors MESH:D009369
138 2461-2469 Disease denotes melanoma MESH:D008545
139 2660-2679 Disease denotes intestinal toxicity MESH:D007410
140 2721-2728 Disease denotes colitis MESH:D003092
141 2859-2874 Disease denotes cystic fibrosis MESH:D003550
142 2881-2899 Disease denotes multiple sclerosis MESH:D009103
143 2910-2916 Disease denotes sepsis MESH:D018805
144 3028-3036 Disease denotes COVID-19 MESH:C000657245
145 3115-3123 Disease denotes COVID-19 MESH:C000657245
146 3167-3173 Disease denotes sepsis MESH:D018805
147 3293-3301 Disease denotes COVID-19 MESH:C000657245
148 3302-3311 Disease denotes infection MESH:D007239
149 3558-3567 Disease denotes mortality MESH:D003643
150 3578-3586 Disease denotes COVID-19 MESH:C000657245
151 3605-3620 Disease denotes lymphocytopenia MESH:D008231
161 3727-3730 Gene denotes Tα1 Gene:134864
162 3825-3828 Gene denotes Tα1 Gene:134864
163 3941-3944 Gene denotes Tα1 Gene:134864
164 4452-4455 Gene denotes Tα1 Gene:134864
165 4697-4708 Gene denotes thioredoxin Gene:7295
166 4921-4924 Gene denotes Tα1 Gene:134864
167 4459-4466 Species denotes E. coli Tax:562
168 5004-5010 Species denotes humans Tax:9606
169 4042-4053 Disease denotes aggregation MESH:D001791
172 5271-5274 Gene denotes Tα1 Gene:134864
173 5419-5426 Species denotes E. coli Tax:562

LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T5 1186-1191 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T6 1336-1342 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T7 1793-1810 Phenotype denotes chronic hepatitis http://purl.obolibrary.org/obo/HP_0200123
T8 1820-1837 Phenotype denotes chronic hepatitis http://purl.obolibrary.org/obo/HP_0200123
T9 2028-2034 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T10 2461-2469 Phenotype denotes melanoma http://purl.obolibrary.org/obo/HP_0002861
T11 2721-2728 Phenotype denotes colitis http://purl.obolibrary.org/obo/HP_0002583
T12 2910-2916 Phenotype denotes sepsis http://purl.obolibrary.org/obo/HP_0100806
T13 3167-3173 Phenotype denotes sepsis http://purl.obolibrary.org/obo/HP_0100806
T14 3605-3620 Phenotype denotes lymphocytopenia http://purl.obolibrary.org/obo/HP_0001888

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T12 0-2 Sentence denotes 1.
T13 3-15 Sentence denotes Introduction
T14 16-134 Sentence denotes Thymosin α1 (Tα1) is an immunostimulatory peptide initially isolated from calf thymus [1] and also abundant in humans.
T15 135-424 Sentence denotes Tα1 is synthesized as the N-terminal moiety of the highly acidic (pI = 3.7) prothymosin α (ProTα), a peculiar cytoplasmic protein due to the absence of any sulfur-containing as well as aromatic side chains and, in particular, its random coil structure under physiological conditions [2,3].
T16 425-570 Sentence denotes Cleaved by the lysosomal asparaginyl endopeptidase (legumain; δ-secretase), the N-terminally acetylated 28-residue peptide Tα1 gets released [4].
T17 571-843 Sentence denotes Tα1 plays a significant role in activating and regulating various cells of the immune system [5], e.g., by stimulating toll-like receptor (TLR)-2 and TLR-9 on myeloid and plasmacytoid dendritic cells (DCs), which results in the secretion of immune-related cytokines [6,7].
T18 844-1011 Sentence denotes Furthermore, Tα1 increases the number of activated T helper (Th) cells and provokes a shift towards the Th1 subclass, thus promoting the cell-mediated immune response.
T19 1012-1206 Sentence denotes In addition, Tα1 was reported to reduce apoptosis of immune cells [8] and to upregulate the expression of major histocompatibility complex I (MHC I) molecules [9] as well as tumor antigens [10].
T20 1207-1516 Sentence denotes Interestingly, Tα1 mediates increased intracellular glutathione (GSH) levels [11], which not only inhibits the growth of certain cancer cells in vitro [7,12], but also blocks the assembly of virus particles by hindering disulfide bond formation that is required for envelope glycoprotein oligomerization [13].
T21 1517-1590 Sentence denotes These features offer a broad range of clinical applications for Tα1 [14].
T22 1591-1739 Sentence denotes In fact, a chemically synthesized Tα1 peptide drug has been marketed for more than 20 years under the trade name Zadaxin™ in more than 30 countries.
T23 1740-1942 Sentence denotes Zadaxin™ is clinically approved for the treatment of chronic hepatitis B (HBV), chronic hepatitis C (HCV), as a vaccine adjuvant, and as adjuvant therapy for chemotherapy-induced immune suppression [7].
T24 1943-2134 Sentence denotes Of note, the use of Tα1 has recently undergone reassessment in the context of modern cancer immunotherapies, as there is indication that this peptide may support immune checkpoint inhibition.
T25 2135-2352 Sentence denotes Preclinical data provide evidence that Tα1 transforms so called cold tumors, which poorly respond to immune checkpoint inhibitors, into highly lymphocyte-infiltrated tumors and, thus, boosts therapeutic efficacy [15].
T26 2353-2624 Sentence denotes Indeed, a retrospective study evaluating clinical phase II data reported an increase in overall survival of melanoma patients receiving sequentially Tα1 and the immune checkpoint inhibitor ipilimumab, a CTLA-4-blocking antibody, compared to ipilimumab therapy alone [16].
T27 2625-2816 Sentence denotes Moreover, Tα1 was shown to prevent intestinal toxicity in a murine model of anti-CTLA-4-induced colitis, hence contributing to an improved safety profile of immune checkpoint inhibitors [17].
T28 2817-2993 Sentence denotes Beyond that, emerging indications such as cystic fibrosis [18], multiple sclerosis [19], and sepsis [20] further emphasize the huge potential of this small therapeutic peptide.
T29 2994-3093 Sentence denotes Finally, with the outbreak of the COVID-19 pandemic, Tα1 recently gained new attention in virology.
T30 3094-3227 Sentence denotes Clinical symptoms of COVID-19 to some extent resemble a pathogen-induced sepsis, which justifies immunomodulatory Tα1 treatment [21].
T31 3228-3443 Sentence denotes Along these lines, Chinese medical staff members at high risk of COVID-19 infection already received a weekly Tα1 injection in combination with human interferon 1 (hIFN-α) nasal drops as a prophylactic measure [22].
T32 3444-3661 Sentence denotes Furthermore, a recent retrospective study in treated Chinese patients revealed that Tα1 significantly reduced the mortality of severe COVID-19 by restoration of lymphocytopenia and reversion of exhausted T cells [23].
T33 3662-3781 Sentence denotes However, there are two major drawbacks of the currently marketed Tα1, both of which are related to its peptidic nature.
T34 3782-3844 Sentence denotes First, the biopharmaceutical production of Tα1 is challenging.
T35 3845-4102 Sentence denotes Apart from the posttranslational modification via N-terminal acetylation, chemical synthesis of Tα1 is complex, and obstacles comprise the large number of required protecting groups as well as the aggregation tendency of intermediates during synthesis [24].
T36 4103-4211 Sentence denotes Furthermore, the overall yield of the solid-phase synthesis is low, typically reaching only around 25% [25].
T37 4212-4328 Sentence denotes On the other hand, the biotechnological production as a recombinant peptide in an economic manner has failed so far.
T38 4329-4483 Sentence denotes Short peptides, in general, are quickly degraded in the bacterial cytoplasm; thus, efficient one-step production of mature Tα1 in E. coli is not feasible.
T39 4484-4714 Sentence denotes An alternative would be expression as part of a larger protein such as natural ProTα [26], as artificial concatamers [27], in fusion with an intein [28] or in fusion with a highly expressed bacterial protein like thioredoxin [29].
T40 4715-4864 Sentence denotes In each case, enzymatic or chemical cleavage is necessary to liberate the mature peptide, which complicates the biopharmaceutical downstream process.
T41 4865-5033 Sentence denotes Second, after administration in vivo, the small peptide Tα1 is quickly eliminated via renal filtration with a terminal plasma half-life in humans of less than 3 h [30].
T42 5034-5138 Sentence denotes This limits its clinical efficacy and, to maintain viable drug levels, would require twice daily dosing.
T43 5139-5427 Sentence denotes In the present study, we applied the PASylation® technology in order to overcome both of these obstacles of the currently available Tα1 drug and to create a long-lasting N-terminally acetylated therapeutic peptide, also offering cheap and efficient biotechnological production in E. coli.
T44 5428-5646 Sentence denotes To this end, we combined fusion with a 600-residue polypeptide comprising the small natural L-amino acids Pro, Ala, and Ser [31] with in situ N-acetylation by overexpressing the host cell N-acetyltransferase RimJ [32].
T45 5647-6002 Sentence denotes The genetically encoded uncharged “PAS” sequence is highly soluble and structurally disordered, with an expanded hydrodynamic volume, thus showing a biophysical behavior very similar to the chemical polymer polyethylene glycol (PEG), which has been utilized for plasma half-life extension of a series of other therapeutic peptides and proteins [33,34,35].