LitCovid-sentences  

PMC:7795856 / 1526-7528 JSONTXT 3 Projects

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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].