LitCovid-sentences  

PMC:7291971 / 2195-9097 JSONTXT 12 Projects

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Id Subject Object Predicate Lexical cue
T20 0-15 Sentence denotes 1 Introduction
T21 16-110 Sentence denotes Emerging RNA viruses are serious threats to public health and have become a worldwide concern.
T22 111-415 Sentence denotes The violent Ebola virus crisis in 2014 [1] (case fatality rate ≈ 50%) and the recurrent outbreaks of Coronaviruses in 2003 (SARS-CoV, case fatality rate ≈ 10% [2]), in 2012 (MERS-CoV, case fatality rate ≈ 36% [3]) and in late december 2019 (SARS-CoV-2) [4] illustrate the critical impact of such viruses.
T23 416-605 Sentence denotes The ongoing COVID-19 pandemic caused by the recently emerged new coronavirus, SARS-CoV-2 [4], is a global health crisis touching every continent (187 countries) with severe economic impact.
T24 606-791 Sentence denotes Most infected people display mild to moderate respiratory illness however patients having co-morbidity factors develop serious illness and pneumonia causing significant mortality [5,6].
T25 792-1081 Sentence denotes This disease endangers 7.7 billion people worldwide with in may 2020 more than 5.3 millions of confirmed cases of infected people and more than 350,000 confirmed deaths, and the number of COVID-19 cases will certainly progress in the next months with a possible rebond of the epidemic [7].
T26 1082-1225 Sentence denotes Despite this important public health threat, there are no yet approved chemotherapeutic agents or vaccines that can prevent or cure infections.
T27 1226-1329 Sentence denotes Therefore, the urgent need of antivirals limiting the coronavirus propagation merits intensive efforts.
T28 1330-1507 Sentence denotes Most of single positive strand RNA viruses have evolved strategies in order to decorate the 5′ end of their own genome by a cap structure mimicking the eukaryotic messenger RNA.
T29 1508-1666 Sentence denotes This structure plays several key biological functions such as protection of RNA from 5′-exoribonucleoases and initiation of the RNA translation into proteins.
T30 1667-1769 Sentence denotes Moreover the cap is a marker of ‘self’ preventing detection by the cellular innate immunity mechanism.
T31 1770-1886 Sentence denotes Thus viruses such as flaviviruses and coronaviruses code for RNA capping pathway mimicking that of eukaryotic cells.
T32 1887-2055 Sentence denotes These viruses produce a subset of enzymatic activities including a RNA 5′-triphosphatase, a guanilyltransferase (GTase) and two RNA cap methyltransferases (MTases) [8].
T33 2056-2438 Sentence denotes After the cap (GpppN) is set by the GTase, a first methylation occurs at N7 position of the guanine by a N7-MTase in the presence of methyl donor S-adenosyl methionine (SAM) yielding to a cap-0 (7mGpppN) followed by a further methylation that is achieved by a 2′-O-MTase at 2′- position of the ribose of the first transcribed nucleotide in RNA yielding cap-1 (7mGpppNm) (Scheme 1 ).
T34 2439-2664 Sentence denotes The N7- and 2′-O-methylation of the viral RNA cap are key events for the viral infection as their inhibition might limit the synthesis of viral proteins and support virus elimination by stimulation of the immune response [9].
T35 2665-2802 Sentence denotes Therefore it is now admitted that the viral MTases are considered as attractive targets for the development of antiviral therapy [10,11].
T36 2803-2948 Sentence denotes Few viral MTase inhibitors have been developed so far, however SAM-mimetics acting as competitors against the MTase co-substrate merit attention.
T37 2949-3146 Sentence denotes Indeed SAM analogs such as sinefungin, 5′-methylthioadenosine (MTA) or S-adenosyl homocysteine (SAH) inhibit most of viral MTases with a potent efficiency but with a total lack of specificity [12].
T38 3147-3341 Sentence denotes This is certainly due to the high conservation of the shape and location of the SAM binding pocket in the human or different viral RNA MTases which share a common Rossman fold organization [13].
T39 3342-3516 Sentence denotes The rarity of specific inhibitors for viral MTases constitutes a stimulating challenge for new antiviral therapy but also for functional studies of these fascinating enzymes.
T40 3517-3649 Sentence denotes Scheme 1 Schematic representation of the 2′-O-methylation of the cap structure at nucleoside N1 at 5′-end of mRNA to form Cap-1 RNA.
T41 3650-3797 Sentence denotes General structure of compounds mimicking the 2′-O-methylation transition state between N1 of mRNA (adenosine in green) and SAM (adenosine in blue).
T42 3798-4073 Sentence denotes With the aim of enhancing specificity of MTase inhibitors, we developed an approach of bisubstrate inhibitors that display a suitable linker between two adenosines that mimic the transition state of the methyl transfer reaction at 2′-O position of the RNA cap structure [12].
T43 4074-4197 Sentence denotes One adenosine is supposed to target the SAM binding site and another adenosine would target the RNA binding site (Fig. 1 ).
T44 4198-4334 Sentence denotes Recently, we described the synthesis of a first series of bisubstrate adenine dinucleosides with various sulfur-containing linkers [14].
T45 4335-4521 Sentence denotes Unexpectedly, such compounds tested at 50 μM or 200 μM concentration failed to inhibit several RNA 2′O-MTases of SARS-CoV, Zika, West Nile, Dengue and Pox viruses such as vaccinia virus.
T46 4522-4692 Sentence denotes Their potential of inhibition toward N7-MTases of SARS-CoV and vaccinia virus was also explored and none of the S-linked dinucleosides was active against these N7-MTases.
T47 4693-4823 Sentence denotes From these data, in the present work we replaced the sulfur atom (S) by a nitrogen atom (N) in the linker between both adenosines.
T48 4824-5070 Sentence denotes This modification presents the advantage of increasing the chemical stability of the linker and offers a possible variability of compounds due to the N-substitution by any chain susceptible to interact with additional protein residues (Scheme 1).
T49 5071-5283 Sentence denotes It is noteworthy that bisubstrate dinucleosides with N-containing linkers have already been reported in transition state analogs of DNA methylation [15] and of RNA methylation at N6 position of adenosine [16,17].
T50 5284-5397 Sentence denotes However, till our work, none viral 2′O-MTase or N7-MTase have been targeted by bisubstrate adenine dinucleosides.
T51 5398-5510 Sentence denotes This observation led us to explore the impact of N-linkers on the antiviral activity of bisubstrate SAM analogs.
T52 5511-5619 Sentence denotes Fig. 1 Rationale for designing a library of bisubstrate compounds for targeting RNA 2′-O-methyltransferases.
T53 5620-5790 Sentence denotes We thus synthesized a new series of transition state analogs of the RNA 2′-O-methylation reaction based on the coupling of a 2′-O-ethyl adenosine to a 5′-amino adenosine.
T54 5791-5986 Sentence denotes We explored a variety of N-substituted linkers in adenine dinucleosides and their inhibition activity was evaluated against several viral RNA 2′O-MTases as well N7-MTases for specificity purpose.
T55 5987-6089 Sentence denotes Unexpectedly, none of the N-linked dinucleosides inhibited any 2′O-MTases of flaviviruses or SARS-CoV.
T56 6090-6295 Sentence denotes However, interestingly some N-nitrobenzenesulfonamide-containing dinucleosides were found to specifically inhibit SARS-CoV N7-MTase nsp14 without inhibiting the cognate human N7-MTase or vaccinia N7-MTase.
T57 6296-6406 Sentence denotes Such specific inhibition results from a high binding affinity of the most potent inhibitors to N7-MTase nsp14.
T58 6407-6535 Sentence denotes In addition, computational docking analysis identified some residues of the binding site for the best inhibitor targeting nsp14.
T59 6536-6902 Sentence denotes As SAM and RNA binding sites of N7-MTase nsp14 are almost completely conserved between SARS-CoV and SARS-CoV-2 (95% sequence homology, Supporting Info Fig. S1) [18], we can forecast that the candidate ligands that are efficient in inhibiting the SARS-CoV functions will be efficient in doing the same for SARS-CoV-2, this emphasizes the interest of the present work.