LitCovid-sentences  

PMC:7461420 / 38597-44867 JSONTXT 10 Projects

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Id Subject Object Predicate Lexical cue
T357 0-58 Sentence denotes 3.1.3 Inhibitors with Michael acceptor as a warhead group
T358 59-316 Sentence denotes The disclosure of the first crystal structure of the SARS‐CoV‐1 Mpro in complex with a peptidic inhibitor Cbz‐Val‐Asn‐Ser‐Thr‐Leu‐Gln‐chloromethyl ketone (also known as hexapeptide chloromethyl ketone; 28) 125 provided clues for the substrate‐based design.
T359 317-592 Sentence denotes Although it is a substrate analog for the porcine transmissible gastroenteritis CoV (TGEV) Mpro, it offers a structural explanation for the P1‐Gln entering into the specific subsite S1 pocket and decreased P2‐leucine specificity in the hydrophobic S2 site of SARS‐CoV‐1 Mpro.
T360 593-763 Sentence denotes Additionally, rupintrivir (29; AG7088), a peptidomimetic inhibitor of human rhinovirus 3C protease is oriented similar to inhibitor 28 in the binding pocket of TGEV Mpro.
T361 764-866 Sentence denotes 129 These two molecules became prototype compounds for the development of SARS‐CoV‐1 Mpro inhibitors.
T362 867-975 Sentence denotes Compound 29 was only weakly active against SARS‐CoV‐1 Mpro (IC50, 800 µM) also in cellular antiviral assays.
T363 976-1089 Sentence denotes 130 However, systematic structural modifications led to a series of analogs that show moderate to good activity.
T364 1090-1212 Sentence denotes 131 For example, compound 30 (Figure 11), in which the P1‐lactam was replaced by a phenyl ring, showed moderate activity.
T365 1213-1322 Sentence denotes Compound 31, in which the larger P2 p‐fluorophenyl was replaced with a phenyl group, was even more effective.
T366 1323-1455 Sentence denotes By taking 29 as a lead, Ghosh et al. designed new molecules mainly focusing on the replacement of the large P2 p‐fluorobenzyl group.
T367 1456-1676 Sentence denotes Two of the resulting structures with P2‐benzyl (32) and prenyl (33) moieties showed decent inhibitory potencies at both enzymatic (K inact, 0.014 and 0.045 min−1, respectively) and cell‐based (IC50, 45 and 70 µM) assays.
T368 1677-1767 Sentence denotes 132 Besides, no cytotoxicity was observed for these compounds up to 100 µM concentration.
T369 1768-1818 Sentence denotes However, 32 and 33 were inactive at MERS‐CoV Mpro.
T370 1819-2011 Sentence denotes 133 The same research group further modified the molecule with the introduction of P4 Boc‐serine, to establish additional hydrogen bond interactions as described in compound 34 (IC50, 75 µM).
T371 2012-2083 Sentence denotes Unfortunately, the activity of the resulting compound was not improved.
T372 2084-2232 Sentence denotes Further modification of the isobutyl group in compound 34 to isoprenyl group in compound 35 displayed potent activity with K i = 3.6 µM (Figure 11).
T373 2233-2235 Sentence denotes 14
T374 2236-2319 Sentence denotes Figure 11 SARS‐CoV Mpro inhibitors containing Michael acceptor as a warhead group.
T375 2320-2427 Sentence denotes Mpro, main protease; SARS‐CoV, severe acute respiratory syndrome coronavirus On the other hand, Yang et al.
T376 2428-2507 Sentence denotes 134 reported a series of peptide inhibitors with a greater inhibitory potency.
T377 2508-2577 Sentence denotes In general, they systematically changed the backbone of inhibitor 29.
T378 2578-2687 Sentence denotes As a result, they were able to identify more specific residues for each subsite (compounds 36–38; Figure 12):
T379 2688-3009 Sentence denotes At first, the P1‐lactam ring was identified as a more specific moiety for the S1‐site, forming multiple hydrogen‐bond interactions with the enzyme as can be seen in the crystal structure (36); P2‐leucine showed a fourfold increased inhibitory activity when compared to the P2‐phenylalanine or ‐4‐fluorophenylalanine (37).
T380 3010-3106 Sentence denotes A lipophilic tert‐butyl residue was recognized to be a better P3‐moiety than the P3‐valine (38).
T381 3107-3241 Sentence denotes Finally, the replacement of P4‐methylisoxazole with a benzyloxy group was the best option for activity enhancement (compare 29 vs 36).
T382 3242-3333 Sentence denotes They all showed moderate to high antiviral activity against HCoV‐229E in cell‐based assays.
T383 3334-3421 Sentence denotes Figure 12 Broad‐spectral antiviral compounds containing a Michael acceptor Shie et al.
T384 3422-3550 Sentence denotes 131 reported another series of peptide inhibitors with comparatively reduced molecular weight to increase drug‐like properties.
T385 3551-3642 Sentence denotes These pseudo‐C2‐symmetric inhibitors consist of a Phe‐Phe‐dipeptidic α,β‐unsaturated ester.
T386 3643-3757 Sentence denotes One of these inhibitors (39) had an outstanding inhibitory activity with an EC50 value of 0.52 µM (see Figure 12).
T387 3758-3840 Sentence denotes Besides, it displayed remarkable antiviral activity with an EC50 value of 0.18 µM.
T388 3841-3955 Sentence denotes Structurally, the presence of 4‐dimethylamine on the phenyl ring was found to be crucial for activity enhancement.
T389 3956-4091 Sentence denotes Another peptidic drug with a Michael acceptor was N3 (40), which was reported to inhibit SARS‐CoV‐1 3CLpro (K i, 9.0 µM) by Yang et al.
T390 4092-4263 Sentence denotes It was observed to be a broad‐spectrum antiviral compound, also inhibiting other CoVs, such as MERS‐CoV Mpro (IC50, 0.28µM), 135 HCoV‐229E, HCoV‐NL63, and HCoV‐HKU1 Mpro.
T391 4264-4386 Sentence denotes 135 , 136 , 137 , 138 It has also exhibited high antiviral activity in an animal model of infectious bronchitis virus.
T392 4387-4430 Sentence denotes 137 The CC50 of 40 is greater than 133 μM.
T393 4431-4501 Sentence denotes SARS‐CoV‐2 shares only 82% of its genome with its relative SARS‐CoV‐1.
T394 4502-4598 Sentence denotes However, essential viral enzymes of both species show sequence similarities of greater than 90%.
T395 4599-4718 Sentence denotes 137 , 139 , 140 , 141 , 142 SARS‐CoV‐2 3CLpro is highly similar to SARS‐CoV‐1 3CLpro, sharing 96% of its sequence.
T396 4719-4814 Sentence denotes Therefore, one could expect that SARS‐CoV‐1 Mpro inhibitors are active against SARS‐CoV‐2 Mpro.
T397 4815-4970 Sentence denotes Compound 40 was found to be active against SARS‐CoV‐2 Mpro and its value of kobs/[I] for the COVID‐19 virus Mpro was determined to be 11 300 ± 880 M−1·s−1.
T398 4971-5063 Sentence denotes 143 Peptide N3 was co‐crystalized with SARS‐CoV‐1 Mpro at 2.1 Å resolution (see Figure 13).
T399 5064-5154 Sentence denotes Its binding mode to SARS‐CoV‐2 Mpro is highly similar to that of other CoV main proteases.
T400 5155-5283 Sentence denotes Some key features include the Cys‐His catalytic dyad and the substrate‐binding pocket situated in a gap between domain I and II.
T401 5284-5470 Sentence denotes Figure 13 The crystal structure of COVID‐19 virus Mpro in complex with N3. (A) Representation of the dimeric Mpro‐inhibitor complex. (B) Surface representation of the homodimer of Mpro.
T402 5471-5624 Sentence denotes Protomer A (blue), protomer B (salmon), compound N3 is presented as green sticks. (C) Schematic view of compound N3 (40) in the substrate‐binding pocket.
T403 5625-5899 Sentence denotes 143 Mpro, main protease [Color figure can be viewed at wileyonlinelibrary.com] In general, inhibitors possessing a Michael acceptor group as a warhead moiety could form an irreversible (covalent) bond with the catalytic cysteine residue in the following manner (Figure 14):
T404 5900-6003 Sentence denotes First, the cysteine residue undergoes 1,4‐addition at the inhibitor's Michael acceptor group (warhead).
T405 6004-6152 Sentence denotes Rapid protonation of the α‐carbanion from His‐H+ leads to the covalent bond formation between the warhead of the inhibitor and the cysteine residue.
T406 6153-6270 Sentence denotes Figure 14 Mechanism of inhibitors with Michael acceptor group [Color figure can be viewed at wileyonlinelibrary.com]