LitCovid-sentences  

PMC:7571312 / 1142-10191 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T8 0-12 Sentence denotes Introduction
T9 13-111 Sentence denotes In late 2019, cases of an unknown respiratory tract infection were first reported in Wuhan, China.
T10 112-566 Sentence denotes By February 2020, the novel coronavirus SARS CoV-2 was identified as the causative agent for COVID-19.1,2 Genome analysis of this virus revealed a high similarity to SARS CoV-1, the coronavirus that caused severe acute respiratory syndrome (SARS) in 2002–2003.2−4 Like SARS CoV-1, which resulted in 799 deaths among the 8464 probable cases,5 SARS CoV-2 can induce fever, coughing, and difficulty breathing that rapidly becomes more serious in some cases.
T11 567-950 Sentence denotes The spread of SARS CoV-2 has been more extensive than that of SARS CoV-1, causing a global pandemic with the current number of worldwide infections surpassing eight million and deaths surpassing 400,000.6 The SARS CoV-1 genome encodes for two large polyproteins pp1a (∼450 kDa) and pp1ab (∼750 kDa) that contain overlapping sequences and include a 3C-like cysteine protease (3CLpro).
T12 951-1299 Sentence denotes The function of this internally encoded 3CLpro is integral to the processing of these proteins and critical for viral replication.7 The SARS CoV-1 3CLpro shares a high degree of structural homology and similar substrate specificity with the coronavirus 3C-like cysteine proteases of hCoV 229E and TGEV8 but is most similar to the SARS CoV-2 3CLpro.
T13 1300-1685 Sentence denotes Specifically, the SARS CoV-1 and SARS CoV-2 share 96% identity between their respective 3CLpro sequences and 100% identity in the active site.8 A recent report by Dai et al. demonstrates that crystallographic information and structure–activity relationships obtained with the SARS CoV-1 3CLpro could facilitate the design of potent SARS CoV-2 3CLpro inhibitors with antiviral potency.9
T14 1686-2068 Sentence denotes There are numerous reports of reversible cysteine protease inhibitors, which include aldehydes,10−13 thio- or oxymethylketones,14 cyclic ketones,15 amidomethylketones,16 nitriles,17,18 or various 1,2-dicarbonyl motifs.19,20 The electrophilic carbon of these chemotypes reacts reversibly with the sulfur atom of an active-site cysteine forming a covalently bound tetrahedral complex.
T15 2069-2482 Sentence denotes Stabilization of this charged protein–ligand transition state by an “oxyanion hole” present in the active site has been observed with certain inhibitor classes by X-ray crystallography and NMR.21,22 A recent report describes the optimization of a series of peptidomimetics designed with an α-ketoamide warhead, which achieves broad-spectrum inhibition against the Mpro for several coronaviruses and enteroviruses.
T16 2483-2701 Sentence denotes Importantly, the reported protease potencies correlate to antiviral potencies, and the authors suggest that the reported SARS CoV-1 3CLpro activity of their lead could be predictive of the SARS CoV-2 3CLpro activity.23
T17 2702-2786 Sentence denotes Alternative modes of enzyme inhibition are covalently bound irreversible inhibitors.
T18 2787-3429 Sentence denotes While chemically reactive affinity labels such as chloromethylketones (CMKs) have demonstrated potent protease inhibition and in certain instances in vivo activity, their inherent chemical reactivity precludes development as clinical agents due to safety concerns.24 However, acyloxymethylketones first reported by Krantz as “quiescent affinity labels” for cathepsin B have demonstrated potent levels of enzyme inhibition with relatively low chemical reactivity.25,26 Mechanistic studies of this class of inhibitors with the cysteine protease caspase-1 support the intermediacy of a thiohemiketal arising from the initial 1,2-carbonyl attack.
T19 3430-3696 Sentence denotes Orientation and stabilization of the acyloxy leaving group within the S1′ domain (Figure 1) of the protease can facilitate SN2 displacement via sulfur migration, resulting in irreversible or bimodal (reversible inhibition followed by slow inactivation) inhibition.27
T20 3697-3761 Sentence denotes Figure 1 Subsite nomenclature for proteolytic enzymes is shown.
T21 3762-3915 Sentence denotes Amino acid residues to the left of the polypeptide scissile amide bond are numbered sequentially, beginning with P1 and increasing toward the N-terminus.
T22 3916-4053 Sentence denotes Amino acid residues to the right of the scissile bond are numbered sequentially, beginning with P1′ and increasing toward the C-terminus.
T23 4054-4141 Sentence denotes Complimentary regions of the protease active site employ the corresponding S numbering.
T24 4142-4423 Sentence denotes Following the SARS outbreak, a CoV-1 3CLpro homology model was published in 2003 with comparisons made to the human rhinovirus (HRV) 3Cpro.28 Although these two proteases share very little sequence conservation, the substrate consensus sequences have a Gln residue in common at P1.
T25 4424-4645 Sentence denotes Analysis of the HRV 3Cpro crystal structure with 1 (rupintrivir; Figure 2) revealed binding interactions that are like those observed for 1 bound to TGEV 3CLpro, which was used in the construction of their homology model.
T26 4646-4795 Sentence denotes The authors concluded that Michael acceptor 1 would serve as a starting point to expedite the identification of a potent SARS CoV-1 3CLpro inhibitor.
T27 4796-5051 Sentence denotes Figure 2 HRV clinical candidate rupintrivir and SARS CoV-1 3CLpro inhibitor 2 employing Michael acceptor-based warheads along with optimized SARS CoV-1 3CLpro inhibitors 3 and 4 containing a carbonyl designed for attack by the catalytic cysteine residue.
T28 5052-5201 Sentence denotes Performing a similar analysis, we tested 1 and additional HRV 3Cpro inhibitors that displayed very weak to unmeasurable SARS CoV-1 3CLpro inhibition.
T29 5202-5376 Sentence denotes Concurrently, new Michael acceptor derivatives were designed that tested P1/P2 alterations and truncation of the P3/P4 binding motif to optimize SARS CoV-1 3CLpro inhibition.
T30 5377-5766 Sentence denotes Compound 2, a derivative that contains an indole capping group at P2, displayed modest levels of irreversible inhibition (kobs/I = 586 ± 11 M–1 s–1) that enabled cocrystallization in complex with SARS CoV-1 3CLpro (PDB code 6XHO).29 Comparison of this structure with the complex of 1 in HRV 3Cpro helped to rationalize the poor performance of the warhead, which had been successful in HRV.
T31 5767-5916 Sentence denotes The structure of the SARS CoV-1 3CLpro complex revealed an eclipsed torsion about the resulting sp3 α,β-carbons from the Michael acceptor (Figure 3).
T32 5917-6055 Sentence denotes Furthermore, the carbonyl oxygen sp2 lone pair electrons are not aligned well with either 3CLpro hydrogen bond donor of the oxyanion hole.
T33 6056-6290 Sentence denotes Specifically, the hydrogen bond between the carbonyl oxygen and the Gly143 NH in the SARS CoV-1 3CLpro complex is 3.4 Å, while the corresponding hydrogen bond distance is a much more favorable 2.8 Å in the complex of 1 with HRV 3Cpro.
T34 6291-6568 Sentence denotes In contrast to these unfavorable interactions, the constrained lactam30 at the P1 site, which was designed to be isosteric with the highly conserved P1 glutamine present in all SARS CoV substrates, is well positioned in the S1 pocket making a favorable hydrogen bond to His163.
T35 6569-6685 Sentence denotes The NH of the lactam is within the hydrogen bond distance to Glu166 and the backbone oxygen of Phe140 in the 3CLpro.
T36 6686-6862 Sentence denotes Additionally, the NH of the indole P2 capping moiety makes a hydrogen bond with the protein backbone while it extends across an otherwise lipophilic surface over the P3 pocket.
T37 6863-6964 Sentence denotes Figure 3 Cocrystal structure of the covalent adduct of 2 bound to SARS CoV-1 3CLpro (PDB code 6XHO).
T38 6965-7036 Sentence denotes The Connolly surface for the inhibitor binding pocket is shown in gray.
T39 7037-7134 Sentence denotes The bonds are represented as the dashed lines, with the bond length measured between heavy atoms.
T40 7135-7255 Sentence denotes The views are centered on warhead with active-site interactions and of complete inhibitor–protein interactions depicted.
T41 7256-7451 Sentence denotes Although the structure of 2 in complex with SARS CoV-1 3CLpro is the final product, the above analysis is expected to apply similarly to the more relevant and structurally close transition state.
T42 7452-7649 Sentence denotes Accordingly, a focused design strategy aimed at replacing the warhead while retaining the P1 lactam and utilizing the methoxy indole capping group in the early rounds of optimization was initiated.
T43 7650-7841 Sentence denotes Specifically, an ideal electrophilic warhead would be bioisosteric, with the scissile amide carbonyl of peptidyl substrates ensuring proper alignment within the oxyanion hole of the protease.
T44 7842-8046 Sentence denotes To better mimic the tetrahedral intermediate generated in the amide bond cleavage, we designed ketone-based covalent reversible and irreversible inhibitors of SARS CoV-1 3CLpro, as illustrated by 3 and 4.
T45 8047-8234 Sentence denotes Compound 4 was selected as a development candidate for SARS CoV-1 but with the successful public health response that ended the 2003 pandemic, the clinical advancement of 4 was suspended.
T46 8235-8442 Sentence denotes Following the COVID-19 outbreak, testing has demonstrated that 4 is a potent inhibitor of the SARS CoV-2 3CLpro (Ki = 0.27 ± 0.1 nM) and a cocrystal structure with 4 bound in the active site has been solved.
T47 8443-8712 Sentence denotes In addition to the potent inhibition of the 3CLpro and viral replication of several coronaviruses, 4 possesses solubility as well as metabolic and chemical stability characteristics, which are consistent with a continuous infusion IV therapeutic treatment for COVID-19.
T48 8713-9049 Sentence denotes We report the research focused on the discovery of reversible and irreversible ketone-based inhibitors of SARS CoV-1 3CLpro employing ligand-protease structures solved by X-ray crystallography, which led to the identification of 4 as a molecule warranting further evaluation for its potential to treat coronaviruses, including COVID-19.