LitCovid-sentences  

PMC:7216760 / 11857-20132 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T47 0-24 Sentence denotes Treating Viral Infection
T48 26-57 Sentence denotes Immunization against SARS-CoV-2
T49 58-145 Sentence denotes The development of a manufacturable, safe, and effective vaccine may take 12–18 months.
T50 146-337 Sentence denotes Several phase I clinical trials are currently recruiting participants to test the safety, reactogenicity, and immunogenicity of several investigational SARS-CoV-2 vaccines (Tables S3 and S4).
T51 338-497 Sentence denotes An mRNA vaccine based on the Spike protein began human clinical trials within a record 63 days from first publication of the SARS-CoV-2 sequence (NCT04283461).
T52 498-885 Sentence denotes It has been suggested that the mutation rate for SARS-CoV-2 is expected to be low, raising hope that a successful vaccine will provide life-long immunity.20 Hyperimmune globulin isolated from the sera of convalescent patients having high titers of antibodies against SARS-CoV-2 or even their whole blood may provide instant “passive” short-lived immunity mainly via viral neutralization.
T53 886-1080 Sentence denotes Antibody dependent therapy, for example targeting the Spike protein might represent the most efficient, near-term therapeutic intervention if regulatory and safety requirements can be addressed.
T54 1081-1353 Sentence denotes With over 1.3 million positive cases of COVID-19 in the US based solely on the results of RNA molecular tests, large-scale antibody testing should be expedited to identify individuals who have been exposed to the virus but were never officially confirmed to have COVID-19.
T55 1354-1544 Sentence denotes An understanding what levels of antibody confer immunity postinfection could be used to determine who may be less likely to transmit the virus and thus may be able to go back safely to work.
T56 1546-1562 Sentence denotes Drug Repurposing
T57 1563-1642 Sentence denotes Developing highly selective SARS-CoV-2 specific new drugs will take many years.
T58 1643-1964 Sentence denotes Alternatively, repurposing of existing, approved drugs can present a more rapid strategy to identifying drugs effective in treating COVID-19 (Tables S3 and S4 and Figure S1).11 Repurposing of drugs that would block SARS-CoV-2 entry and/or replication are urgently needed to mitigate the symptomatic burden of the disease.
T59 1965-2217 Sentence denotes Unfortunately, the HIV protease inhibitors ritonavir/liponavir failed to show efficacy in SARS-CoV-2 infected patients.21 Hydroxychloroquine, which may act by increasing the pH within lysosomes, was granted FDA authorization for use in emergency cases.
T60 2218-2544 Sentence denotes Several antiviral agents are being tested such as the RdRp inhibitor remdesivir and the approved anti-influenza drug faviprivir.8 Remdesivir was previously tested in humans with Ebola virus disease and also in animal models of MERS and SARS-CoV.11 At least six clinical trials are evaluating remdesivir in SARS-CoV-2 patients.
T61 2545-2633 Sentence denotes Other drugs that might inhibit RdRp include the broad-spectrum antiviral drug ribavirin.
T62 2634-2739 Sentence denotes RdRp conservation among RNA virus families makes it an exciting target for the discovery of newer agents.
T63 2740-2865 Sentence denotes The Spike protein, ACE2, and TMPRSS2 may also represent interesting therapeutic targets for current drug repurposing efforts.
T64 2866-3286 Sentence denotes Camostat mesylate, approved in Japan for treatment of pancreatic inflammation, has been shown to block TMPRSS2 activity.22 Arbidol, which is hypothesized to block Spike/ACE2 binding, is being investigated clinically, and a clinical trial was recently launched to study the effect of thiazide, thiazide-like diuretics, calcium channel blockers, ACE inhibitors, and angiotensin receptor blockers in COVID-19 (NCT04330300).
T65 3287-3466 Sentence denotes The availability of soluble recombinant hACE2 encouraged its testing in two clinical trials; although one was terminated (NCT04287686) the other is currently active (NCT04335136).
T66 3467-3816 Sentence denotes Monoclonal antibodies, especially for interleukin-6 (IL-6) or its receptor, are also being considered for the control of SARS-CoV-2 associated respiratory exacerbations.11 Interestingly, several Janus Kinase (JAK) inhibitors such as baricitinib and ruxolitinib are currently being evaluated given their involvement in interleukin signaling pathways.
T67 3817-3950 Sentence denotes Another currently recruiting clinical trial is testing quinolone, macrolide, and β-lactam antibiotics against COVID-19 (NCT02735707).
T68 3951-4061 Sentence denotes Multiple groups have tested FDA approved drugs in various in vitro assays as well as in computational screens.
T69 4062-4425 Sentence denotes Many of these drugs show inhibitory activities, although not always at a concentration that may be safely achieved in patients.23 Controlled clinical trials of these agents are mandatory to assess their efficacy and safety without creating false positive hope or depleting the supplies of drugs needed to treat the diseases for which they were initially approved.
T70 4427-4439 Sentence denotes Novel Agents
T71 4440-5383 Sentence denotes Mpro and PLpro are cysteine proteases responsible for the cleavage of viral polypeptides into functional proteins for virus replication and packaging within host cells.24 These enzymes represent the best characterized drug targets among coronaviruses and are currently the focus of attention among scientists seeking novel coronavirus small molecule therapeutics.25 Mpro is shared by all coronavirus genera and has similarity to the 3Cpro of the Enterovirus genus in the picornavirus family.24 Mpro contains a Cys···His catalytic dyad with an additional α-helical domain involved in the dimerization of the protease, which is essential for its catalytic activity.25 The enteroviral 3Cpro functions as a monomer featuring a classical Cys···His···Glu/Asp catalytic triad.24 Yet, they share the almost absolute requirement for Gln in the P1 position of the substrate and space for only small residues such as Gly, Ala, or Ser in the P1′ position.
T72 5384-6132 Sentence denotes Since no human proteases with a similar cleavage specificity are known, it may be possible to identify highly selective Mpro/3Cpro inhibitors, which display minimal inhibition of host proteases.26 The 3-D structures of unliganded SARS-CoV-2 Mpro and of its complex with a peptidomimetic α-ketoamide inhibitor (11r) have been solved26 and were used to support the design of an optimized derivative (13b) through docking studies (Figure S2). α-Ketoamides can interact with the catalytic center of Mpro through two hydrogen bonding interactions rather than only one as with other warheads such as aldehydes or Michael acceptors.24 Nucleophilic attack of the α-keto group by the catalytic Cys residue results in reversible formation of a thiohemiketal.
T73 6133-6508 Sentence denotes These α-ketoamides feature a 5-membered rigid γ-lactam as a mimic of the P1 residue, glutamine, required for Mpro specificity, with the advantage of reducing the loss of entropy upon binding.24 Follow up optimization efforts guided by docking to the SARS-CoV-2 Mpro co-crystal structure with 11r, included incorporation of the P3-P2 amide bond into a pyridone ring as in 13a.
T74 6509-6701 Sentence denotes The resulting half-life of 13a in plasma was enhanced by 3 fold relative to 11r, in vitro kinetic plasma solubility improved by a factor of ∼19 and thermodynamic solubility by a factor of ∼13.
T75 6702-6950 Sentence denotes 13a inhibited purified recombinant SARS-CoV-2 Mpro, SARS-CoV Mpro, and MERS-CoV Mpro in the submicromolar range.26 Modification of the P1′ and P3 moieties of 13a afforded an optimized derivative 13b which was crystallized with SARS-CoV-2 Mpro (PDB:
T76 6951-6966 Sentence denotes 6Y2G and 6Y2F).
T77 6967-7039 Sentence denotes Both 13a and 13b displayed good stability in mouse and human microsomes.
T78 7040-7139 Sentence denotes 13b (3 mg/kg) showed longer t1/2, tmax, and residence time compared to 13a (20 mg/kg) in CD-1 mice.
T79 7140-7209 Sentence denotes Both compounds showed lung tropism which is thought to be beneficial.
T80 7210-7452 Sentence denotes While the development of these ketoamides into clinical candidates requires additional safety studies, the availability of their crystal structures is of great importance in facilitating the discovery and development of other Mpro inhibitors.
T81 7453-7612 Sentence denotes One of the suggested agents for testing is the previously reported Rhinovirus and SARS-CoV Mpro inhibitor clinical candidate rupintrivir (AG-7088) (Figure S2).
T82 7613-7749 Sentence denotes In addition, other groups recently reported Mpro crystal structures with inhibitors such as the peptidomimetic Michael acceptor N3 (PDB:
T83 7750-7794 Sentence denotes 6LU7) and the reversible inhibitor X77 (PDB:
T84 7795-8013 Sentence denotes 6W63) (Figure S2).27 A large array of Mpro crystal structures with multiple covalent and noncovalent fragments were solved through an exceptionally large screen with vast opportunities for fragment growing and merging.
T85 8014-8275 Sentence denotes The cryo EM structure of SARS-CoV-2 RdRp was recently solved, showing nearly an identical sequence to its SARS-CoV homologue.28 RdRp should be another high priority target for therapeutic intervention given that lead inhibitors such as remdesivir already exist.