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PMC:7795856 / 14271-23327 JSONTXT

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LitCovid-PubTator

Id Subject Object Predicate Lexical cue tao:has_database_id
262 277-284 Species denotes E. coli Tax:562
263 643-650 Species denotes E. coli Tax:562
269 856-863 Gene denotes insulin Gene:3630
270 986-989 Gene denotes Tα1 Gene:134864
271 1543-1546 Gene denotes Tα1 Gene:134864
272 1166-1169 Chemical denotes PAS
273 1223-1227 Chemical denotes RimJ
281 2237-2240 Gene denotes Tα1 Gene:134864
282 2485-2499 Gene denotes growth hormone Gene:2688
283 2501-2504 Gene denotes hGH Gene:8836
284 2540-2543 Gene denotes hGH Gene:8836
285 2479-2484 Species denotes human Tax:9606
286 2641-2648 Species denotes E. coli Tax:562
287 1908-1911 Chemical denotes SDS MESH:D012967
302 2744-2747 Gene denotes Tα1 Gene:134864
303 3118-3131 Gene denotes serum albumin Gene:213
304 3196-3199 Gene denotes Tα1 Gene:134864
305 3482-3485 Gene denotes Tα1 Gene:134864
306 4289-4292 Gene denotes Tα1 Gene:134864
307 4402-4405 Gene denotes Tα1 Gene:134864
308 4534-4537 Gene denotes Tα1 Gene:134864
309 2914-2918 Species denotes rats Tax:10116
310 3112-3117 Species denotes human Tax:9606
311 2710-2713 Chemical denotes PAS
312 2968-2975 Chemical denotes Tα1-PAS
313 3390-3424 Chemical denotes arginylglycylaspartic acid peptide
314 3297-3302 Disease denotes tumor MESH:D009369
315 4326-4332 Disease denotes cancer MESH:D009369
324 4725-4728 Gene denotes Tα1 Gene:50719
325 4959-4962 Gene denotes Tα1 Gene:50719
326 4919-4938 Species denotes Sprague–Dawley rats Tax:10116
327 5225-5231 Species denotes humans Tax:9606
328 5640-5647 Species denotes patient Tax:9606
329 5007-5043 Chemical denotes methoxypolyethylene glycol maleimide
330 5073-5076 Chemical denotes Cys MESH:D003545
331 5395-5406 Disease denotes hepatitis B MESH:D006509
340 6065-6068 Gene denotes Tα1 Gene:134864
341 6005-6011 Species denotes humans Tax:9606
342 6117-6119 Disease denotes PD MESH:D010300
343 6210-6225 Disease denotes cystic fibrosis MESH:D003550
347 6296-6302 Disease denotes cancer MESH:D009369
359 6811-6826 Gene denotes thymosin beta 4 Gene:7114
360 6840-6866 Gene denotes C-type natriuretic peptide Gene:4880
361 6868-6871 Gene denotes CNP Gene:4880
362 6885-6904 Gene denotes parathyroid hormone Gene:5741
363 6906-6909 Gene denotes PTH Gene:5741
364 6934-6957 Gene denotes glucagon-like peptide-1 Gene:2641
365 6959-6964 Gene denotes GLP-1 Gene:2641
366 7442-7464 Gene denotes dipeptidyl peptidase-4 Gene:1803
367 7466-7472 Gene denotes DPP-IV Gene:1803
368 7512-7517 Gene denotes GLP-1 Gene:2641
369 6879-6884 Species denotes human Tax:9606
385 7919-7924 Gene denotes GLP-1 Gene:2641
386 7929-7932 Gene denotes GIP Gene:2695
387 7941-7944 Gene denotes Tα1 Gene:134864
388 7949-7955 Gene denotes GM-CSF Gene:1437
389 8264-8267 Gene denotes Tα1 Gene:134864
390 8928-8934 Species denotes yeasts Tax:4932
391 8939-8948 Species denotes mammalian Tax:9606
392 8401-8410 Species denotes synthetic Tax:2005392
393 8086-8112 Chemical denotes arginylglycylaspartic acid MESH:C047981
394 8314-8318 Chemical denotes Gly4 MESH:C046274
395 8411-8414 Chemical denotes PEG MESH:D011092
396 8485-8488 Chemical denotes PAS
397 8847-8855 Chemical denotes peptides MESH:D010455
398 8192-8197 Disease denotes tumor MESH:D009369
399 8277-8282 Disease denotes tumor MESH:D009369

LitCovid-PD-HP

Id Subject Object Predicate Lexical cue hp_id
T15 3297-3302 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T16 4326-4332 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T17 5387-5404 Phenotype denotes chronic hepatitis http://purl.obolibrary.org/obo/HP_0200123
T18 6254-6260 Phenotype denotes sepsis http://purl.obolibrary.org/obo/HP_0100806
T19 6270-6276 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T20 6296-6302 Phenotype denotes cancer http://purl.obolibrary.org/obo/HP_0002664
T21 8192-8197 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664
T22 8277-8282 Phenotype denotes tumor http://purl.obolibrary.org/obo/HP_0002664

LitCovid-sentences

Id Subject Object Predicate Lexical cue
T87 0-2 Sentence denotes 3.
T88 3-13 Sentence denotes Discussion
T89 14-214 Sentence denotes The present data demonstrate that the PASylation technology can solve two major problems of a peptide drug: (i) instability in the expression host and (ii) low bioactivity due to fast renal clearance.
T90 215-456 Sentence denotes Typically, small peptides, if expressed in a soluble state in E. coli, are quickly degraded by host cell proteases [42] and, thus, require production as larger fusion proteins as well as subsequent release by site-specific cleavage in vitro.
T91 457-699 Sentence denotes Here, fusion with a random-coil forming PAS sequence of ~600 amino acids prevented proteolytic degradation and allowed cost-efficient one-step production of the intact fusion protein in E. coli without the need of additional processing steps.
T92 700-1126 Sentence denotes Of note, in contrast to classical approaches, which involve the use of an insoluble fusion partner, for example, an α-galactosidase fragment in the case of insulin [43], to provoke formation of inclusion bodies and protect the gene product from intracellular proteolysis, the PASylated Tα1 peptide was recovered as a soluble fusion protein, thus allowing direct purification from the cell extract without solubilization steps.
T93 1127-1251 Sentence denotes Furthermore, the C-terminally attached PAS moiety was compatible with N-terminal acetylation by RimJ as confirmed by ESI-MS.
T94 1252-1580 Sentence denotes Yields of our expression study at the research scale reached 15 mg purified acetylated Tα1-PAS and even 50 mg PAS-Tα1 per 1 L bacterial culture (at an optical density (OD) of 3), which surpasses the reported yield of a bacterially produced (yet probably non-acetylated and non-glycosylated) Tα1-Fc fusion protein (16 mg/L) [44].
T95 1581-1822 Sentence denotes Still, there is considerable opportunity of improvement for both versions of the PASylated peptide by optimizing the expression plasmid and the production process, including high cell density fermentation under controlled feeding conditions.
T96 1823-2014 Sentence denotes Apart from that, the absence of a prominent band for the co-expressed enzyme RimJ in SDS-PAGE despite approximately 50% N-terminal acetylation of Tα1-PAS also indicates room for amelioration.
T97 2015-2245 Sentence denotes Optimization of the ribosome-binding site preceding the RimJ cistron or changing the order within the bicistronic operon should boost biosynthesis of the enzyme and result in increased yield of the N-terminally acetylated Tα1-PAS.
T98 2246-2511 Sentence denotes Finally, the use of a high-efficiency secretory bacterial expression system such as ESETEC [45] or CORYNEX [46,47] should lead to higher product titers as previously demonstrated for other PASylated fusion proteins such as PASylated human growth hormone (hGH) [48].
T99 2512-2691 Sentence denotes The yield of functional PAS-hGH was more than 100-fold higher with the ESETEC system than in a conventional laboratory strain of E. coli, reaching several grams per liter culture.
T100 2692-2841 Sentence denotes Attachment of the PAS sequence at either end of the Tα1 peptide increased the hydrodynamic volume by more than an order of magnitude as shown by SEC.
T101 2842-3068 Sentence denotes This strongly expanded molecular size resulted in a plasma half-life in rats of around 16 h after a subcutaneous injection of Tα1-PAS, which is more than an 8-fold increase compared to the unmodified peptide drug (1.9 h) [41].
T102 3069-3266 Sentence denotes Based on in vitro cell culture assays with human serum albumin fusion proteins [49], both the C-terminus and the N-terminus of Tα1 should be permissible to modification while retaining bioactivity.
T103 3267-3457 Sentence denotes This was also shown in animal tumor models for C-terminal fusion with an immunoglobulin Fc fragment [41], an internalizing arginylglycylaspartic acid peptide iRGD [50], and thymopentin [51].
T104 3458-3705 Sentence denotes However, in the case of Tα1, some caution is appropriate regarding the significance of in vitro cell culture assays as its mode of action is complex and involves different receptors provoking multiple biological effects on various cell types [52].
T105 3706-3898 Sentence denotes Second, a prolonged circulation in the body as demonstrated here via application of the PASylation technology influences both binding kinetics and bioactivity, which is not reflected in vitro.
T106 3899-4273 Sentence denotes While attachment of large macromolecules, such as PAS polypeptides or albumin, but also PEG [53], can lead to lower receptor association rates for bioactive peptides or proteins, this is usually overcompensated by the drastically prolonged in vivo half-life, which results in a strongly enhanced bioactivity as demonstrated for multiple PASylated biopharmaceuticals [37,54].
T107 4274-4432 Sentence denotes In the case of Tα1, superior effects in preclinical cancer models due to prolonged circulation were recently demonstrated for a Tα1-Fc fusion protein [41,44].
T108 4433-4648 Sentence denotes Such studies would be the obvious next step to investigate enhanced in vivo bioactivity of PASylated Tα1, and it will be interesting to see whether its N-terminally or C-terminally PASylated version performs better.
T109 4649-4944 Sentence denotes In comparison with other published approaches to prolong the circulation of Tα1, the measured terminal half-life of Tα1-PAS is even longer than the value of around 8.2 h reported for a corresponding PEGylated peptide after an intravenous injection into the tail vein of Sprague–Dawley rats [55].
T110 4945-5085 Sentence denotes This modified Tα1 was prepared by chemically coupling a 5 kDa methoxypolyethylene glycol maleimide via an engineered N-terminal Cys residue.
T111 5086-5322 Sentence denotes Of note, according to the rules of allometric scaling, a much longer half-life in the range of several days can be expected for Tα1-PAS in humans [56,57], which would allow weekly dosing while achieving a lasting pharmacological effect.
T112 5323-5567 Sentence denotes According to the prescription information for Zadaxin™ to treat chronic hepatitis B, the recommended dose for the monotherapy, or the combination therapy with interferon, is a 1.6 mg subcutaneous injection twice weekly over 6 months (52 doses).
T113 5568-5678 Sentence denotes Consequently, weekly or biweekly injections would considerably decrease patient burden and improve compliance.
T114 5679-5893 Sentence denotes Moreover, a more continuous plasma level above the minimum effective dose due to slower clearance, as illustrated by the drastically increased AUC, should boost in vivo efficacy and open new treatment perspectives.
T115 5894-6282 Sentence denotes Especially in preclinical animal models, which typically suffer from a much quicker drug clearance compared to humans [37] owing to their smaller body size, a long-acting Tα1 should lead to more convincing pharmacodynamic (PD) effects and pave the way for biopharmaceutical development for novel indications such as cystic fibrosis [18], HIV-1 infection [58], sepsis [20], or cancer [59].
T116 6283-6421 Sentence denotes For example, cancer studies have demonstrated that high doses of the conventional peptide are required to achieve antitumor activity [60].
T117 6422-6541 Sentence denotes The beneficial application of the PASylation technology demonstrated in this work can be transferred to other peptides.
T118 6542-6757 Sentence denotes There are more than 7000 naturally occurring peptides covering a wide range of physiological functions [61], including many peptides with proven therapeutic potential, which could profit from the presented approach.
T119 6758-6987 Sentence denotes Examples are therapeutically active peptides such as thymosin beta 4 [62,63], the C-type natriuretic peptide (CNP) [64], human parathyroid hormone (PTH) [65], relaxin [66], or glucagon-like peptide-1 (GLP-1) and its analogs [67].
T120 6988-7215 Sentence denotes Today, it is generally recognized that intrinsic weaknesses of this drug class, such as poor stability and short circulating plasma half-life, need to be addressed in order to transform peptides into efficacious medicines [61].
T121 7216-7324 Sentence denotes The approach described here, N- or C-terminal PASylation, optionally combined with acetylation, solves both.
T122 7325-7523 Sentence denotes On the one hand, N-terminal acetylation protects peptides from proteolytic degradation by exoproteases, for example, dipeptidyl peptidase-4 (DPP-IV), as shown for N-terminally acetylated GLP-1 [68].
T123 7524-7763 Sentence denotes On the other hand, PASylation increases the hydrodynamic volume of the peptide above the pore size of the glomerular basement membrane, hence retarding kidney filtration and prolonging the pharmacodynamic effect of its fusion partner [31].
T124 7764-7836 Sentence denotes Furthermore, PASylation can serve as a linker to join two peptides [69].
T125 7837-7961 Sentence denotes This is of particular interest if both entities act synergistically, for example, GLP-1 and GIP [70] or Tα1 and GM-CSF [71].
T126 7962-8227 Sentence denotes Alternatively, the biologically active protein/peptide can be linked via the PAS sequence to a targeting domain such as the arginylglycylaspartic acid peptide RGD peptide which binds to integrins αVβ3 and αVβ5 in order to enhance tumor penetration and accumulation.
T127 8228-8385 Sentence denotes In fact, fusion of the short-acting Tα1 with the tumor-targeting iRGD peptide using a Gly4 linker has recently demonstrated enhanced antitumor activity [50].
T128 8386-8558 Sentence denotes In contrast to synthetic PEG linkers, which are commonly used for bioconjugations, the recombinant PAS sequence exhibits a precisely defined size and is biodegradable [72].
T129 8559-8738 Sentence denotes The PAS polypeptide itself is stable in blood plasma but quickly degraded by intracellular enzymes, thus avoiding organ accumulation [31], a well-known effect for PEGylation [73].
T130 8739-9056 Sentence denotes Moreover, PAS sequences are non-immunogenic in animals [31,74] and offer a one-step production of PASylated peptides in various commercially scalable expression systems including bacteria, yeasts, or mammalian cells [35,48], which would even allow the preparation of peptides carrying posttranslational modifications.