LitCovid-sentences  

PMC:7029759 / 17050-23977 JSONTXT 15 Projects

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Id Subject Object Predicate Lexical cue
T106 0-42 Sentence denotes Blocking agents that bind to ACE2 receptor
T107 43-138 Sentence denotes The first strategy would consist of administering to patients an agent that would bind to ACE2.
T108 139-280 Sentence denotes The key advantage here is that the host ACE2 protein will not change, so there is no concern about escape from binding the therapeutic agent.
T109 281-489 Sentence denotes Moreover, the virus will not have the ability to mutate and bind an entirely new host receptor in the time frame of this outbreak; such functional relationships are established by evolution over long periods.
T110 490-692 Sentence denotes By analogy, the influenza virus changes the mutations on its surface to escape antibody neutralization every year, but it always focuses on using sialic acid on the cell surface as an entry receptor 43.
T111 693-748 Sentence denotes There are two known options for agents to bind to ACE2.
T112 749-918 Sentence denotes The first is using the small receptor-binding domain (RBD) from the SARS S protein that has been shown to be the key domain that binds the ACE2 receptor during entry 44.
T113 919-1048 Sentence denotes Administration of this domain, 193 amino acids in size, has been shown to effectively block the entry of SARS in cell culture 44.
T114 1049-1202 Sentence denotes It is well within reason that SARS RBD could be given to patients, thereby binding their ACE2 proteins on target cells, preventing infection ( Figure 1).
T115 1203-1312 Sentence denotes There is also the potential for the equivalent RBD of 2019-nCoV to be produced and used as a therapy as well.
T116 1313-1682 Sentence denotes This strategy assumes SARS and 2019-nCoV share the same binding site on ACE2, which is highly likely given the similar ACE2 binding sites of SARS and NL63 coronavirus The small size of the therapy, similar in size in nanobody domains from camelid antibodies, would enhance the perfusion of the biologic into tissues to more effectively bind to viral entry receptors 45.
T117 1683-1866 Sentence denotes In regards to the outbreak situation that is ongoing, the small protein facilitates the rapid production of the therapy in bacteria potentially, which would help production yields 19.
T118 1867-2067 Sentence denotes Moreover, bacterial production would allow RBD proteins to be produced in a wide range of production facilities today in China, which already has numerous contract research organization operations 46.
T119 2068-2226 Sentence denotes Alternatively, the RBD protein could be attached to an Fc fragment for extended circulation, which was done for an equivalent 212 amino acid domain from MERS.
T120 2227-2412 Sentence denotes The MERS RBD-Fc fusion demonstrated the ability to block viral infection toward cell receptors, as well as to stimulate an immune response against that specific viral domain in mice 47.
T121 2413-2588 Sentence denotes Of note, since the RBD-Fc fusion would bind to normal cells, one would want to eliminate cytotoxic Fc domain functions through mutations that eliminate Fc receptor binding 48.
T122 2589-2598 Sentence denotes Figure 1.
T123 2600-2678 Sentence denotes Therapeutic agents that could be used to block 2019-nCoV from infecting cells.
T124 2679-2768 Sentence denotes Target cells expressing ACE2 include lung and gastrointestinal tissues in the human body.
T125 2769-2882 Sentence denotes The large spike protein on the surface of the coronavirus binds to ACE2 on infected cells, leading to cell entry.
T126 2883-2963 Sentence denotes Three proposed strategies would block this interaction would abrogate infection.
T127 2964-3131 Sentence denotes In the first, the receptor-binding domain (RBD) of the spike protein from SARS or 2019-nCoV would be administered, thereby binding ACE2 and saturating available sites.
T128 3132-3258 Sentence denotes Alternatively, an antibody or single chain antibody fragment (scFv) could be administered against ACE2 to accomplish the same.
T129 3259-3394 Sentence denotes A third strategy would target the coronavirus virions directly by using the ACE2 extracellular domain as bait to bind to spike protein.
T130 3395-3487 Sentence denotes An Fc domain fused to ACE2 would facilitate prolonged circulation of the biologic (ACE2-Fc).
T131 3488-3634 Sentence denotes A second, similar strategy would be to administer an antibody that would bind to ACE2 protein, thereby preventing 2019-nCoV infection ( Figure 1).
T132 3635-3725 Sentence denotes This strategy was shown to effectively block SARS entry and replication in experiments 42.
T133 3726-3902 Sentence denotes While no ACE2 antibody sequences are published in literature indexes, monoclonal antibodies do exist and the associated hybridoma sequences could be cloned in a matter of days.
T134 3903-4054 Sentence denotes There would be no concern for any viral escape from an ACE2 binding antibody, which is an advantage over neutralizing approaches against the S protein.
T135 4055-4160 Sentence denotes There are a couple of design considerations when thinking about how to employ the ACE2 antibody strategy.
T136 4161-4312 Sentence denotes Any effector functions would need to be removed from the Fc domain 49, such that inflammation would not be caused in different tissues expressing ACE2.
T137 4313-4407 Sentence denotes This would retain the long-half life endowed by the Fc domain without any of the side effects.
T138 4408-4650 Sentence denotes The downside of including the Fc domain is the need to use a more expensive mammalian cell production system to preserve proper glycosylation, which would decrease the turnaround time for getting the drug to patients in the outbreak scenario.
T139 4651-4751 Sentence denotes Alternatively, one could just administer a single chain variable fragment (scFv) that binds to ACE2.
T140 4752-4826 Sentence denotes A nanobody or VHH domains from camelids are another option as well 50, 51.
T141 4827-4939 Sentence denotes These could be produced in bacteria, and its small size would allow for rapid permeation into different tissues.
T142 4940-5019 Sentence denotes The downside is the shorter half-life of these molecules without the Fc domain.
T143 5020-5071 Sentence denotes There are several limitations to these two options.
T144 5072-5356 Sentence denotes Regarding the SARS RBD strategy, the body would likely develop an immune response to the SARS protein eventually, although the key intervention period of infection to combat 2019-nCoV would fall under this window of time, where after an immune response for both viruses would develop.
T145 5357-5560 Sentence denotes Alternatively, if one were to use the homologous RBD from 2019-nCoV itself, this immune response would likely be very advantageous since it could yield both a blocking effect and a vaccination effect 52.
T146 5561-5790 Sentence denotes For both strategies, the dose that would be needed to block ACE2 receptors in the body across different organs is unknown, and as is the percentage of ACE2 receptors that would need to be saturated in order to slow the infection.
T147 5791-6000 Sentence denotes The number of ACE2 receptors in the body, which are found in lung and gastrointestinal organs along with vascular endothelial cells among other tissues 53, could ultimately prove prohibitive for this strategy.
T148 6001-6150 Sentence denotes Moreover, the turnover of the ACE2 receptor on the cell surface would also influence how often the therapeutic protein would need to be administered.
T149 6151-6328 Sentence denotes To solve this issue, one could increase the concentration of anti-ACE2 therapy at the crucial site of infection in the lungs, via local administration to lungs via nebulization.
T150 6329-6454 Sentence denotes Lastly, there is the possibility that binding ACE2 directly could paradoxically worsen lung physiology and clinical symptoms.
T151 6455-6669 Sentence denotes A study found that a fusion protein of SARS RBD to Fc domain bound ACE2 in murine lung tissue after administration, exacerbating alveolar edema via ACE2 interaction, which normally counteracts acute lung injury 54.
T152 6670-6837 Sentence denotes This suggests that if one were use an ACE2 binding strategy, it would be best employed early during infection or as a prophylaxis to block the initial viral infection.
T153 6838-6927 Sentence denotes Ultimately, clinical trials in patients would need to investigate these potential issues.