LitCovid-sentences  

PMC:7600245 / 28416-38432 JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T206 0-2 Sentence denotes 3.
T207 3-28 Sentence denotes Viral Protease Inhibitors
T208 30-34 Sentence denotes 3.1.
T209 35-64 Sentence denotes Lopinavir/Ritonavir (Kaletra)
T210 65-214 Sentence denotes Lopinavir (Figure 6) is an orally bioavailable, small peptidomimetic antiretroviral agent that acts as an HIV-1 aspartate competitive inhibitor [83].
T211 215-350 Sentence denotes The drug inhibits the cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV.
T212 351-445 Sentence denotes The inhibition eventually results in the formation of immature, noninfectious viral particles.
T213 446-479 Sentence denotes The drug was approved by the U.S.
T214 480-587 Sentence denotes FDA in combination with ritonavir (Figure 6), which is another antiretroviral aspartate protease inhibitor.
T215 588-790 Sentence denotes Ritonavir does not only provide an additive effective, but it is also a pharmacokinetic booster, i.e., it inhibits the CYP3A-mediated metabolism of lopinavir and thus increases its plasma level [83,84].
T216 791-1125 Sentence denotes Currently, lopinavir/ritonavir is being evaluated for the treatment of SARS-CoV-2 patients in more than 35 interventional trials alone or in conjugation with hydroxychloroquine, inhaled INF-α, INF-β 1b and hydroxychloroquine, or oseltamivir (an inhibitor of neuraminidase in influenza virus) (for details refer to clinicaltrials.gov).
T217 1126-1194 Sentence denotes The rationale for using lopinavir is attributed to multiple studies.
T218 1195-1325 Sentence denotes Lopinavir exhibited an antiviral activity against SARS-CoV-2 virus in Vero E6 cells with an estimated EC50 value of 26.63 μM [85].
T219 1326-1470 Sentence denotes Computational studies have also suggested that lopinavir may inhibit the viral main protease Mpro, perhaps by targeting its active site [86,87].
T220 1471-1561 Sentence denotes Earlier, lopinavir exhibited in vitro activity against SARS-CoV-1 and MERS-CoV [88,89,90].
T221 1562-1652 Sentence denotes It also showed beneficial effects in animal studies for the treatment of MERS-CoV [91,92].
T222 1653-1814 Sentence denotes Furthermore, there is an evidence of some clinical benefit for lopinavir/ritonavir when used with ribavirin and/or INFs against MERS-CoV and SARS-CoV [88,93,94].
T223 1815-1974 Sentence denotes Yet, coronavirus proteases, including Mpro, do not have a C2-symmetric protein architecture which is the target of lopinavir and all HIV-1 protease inhibitors.
T224 1975-2082 Sentence denotes This subsequently sheds doubts on the prospect of HIV-1 aspartate protease inhibitors in treating COVID-19.
T225 2083-2347 Sentence denotes In this direction, a randomized, open-label trial in China in COVID-19 patients (n = 199), who were hospitalized with severe illness, compared lopinavir/ritonavir (400 mg/100 mg twice a day for 14 days) along with the standard care to the standard care alone [94].
T226 2348-2645 Sentence denotes The trial found that the time to achieve clinical improvement was similar in the two groups and that no statistically significant improvement, with respect to the viral load, oxygen therapy duration, hospitalization duration, or time to death, was achieved by the use of the drug combination [95].
T227 2646-2795 Sentence denotes Furthermore, a retrospective cohort study in China evaluated the use of lopinavir/ritonavir with or without umifenovir in COVID-19 patients (n = 16).
T228 2796-2990 Sentence denotes On the seventh day, SARS-CoV-2 was not detected in the nasopharyngeal specimens of 35% of lopinavir/ritonavir-treated patients compared to 75% of lopinavir/ritonavir/umifenovir-treated patients.
T229 2991-3086 Sentence denotes Chest computerized tomography scans were also better in the latter group (29% versus 69%) [96].
T230 3087-3372 Sentence denotes Moreover, a randomized, open-label trial in COVID-19 adults (n = 127) with mild to moderate symptoms in Hong Kong suggested that adding ribavirin and INF-β-1b to lopinavir/ritonavir increased the efficacy of the treatment when it was initiated within 7 days of the symptoms onset [59].
T231 3373-3501 Sentence denotes Other studies also suggested a limited benefit of lopinavir/ritonavir with or without INFs in patients with COVID-19 [97,98,99].
T232 3502-3835 Sentence denotes Recently, a small, randomized study in hospitalized COVID-19 adults (n = 22) in China compared lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days) against chloroquine (500 mg twice daily for 10 days) and found that chloroquine was linked to a shorter time to RT-PCR conversion and a faster recovery [100].
T233 3837-3841 Sentence denotes 3.2.
T234 3842-3874 Sentence denotes Darunavir/Cobicistat (Prezcobix)
T235 3875-3994 Sentence denotes Darunavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease [101,102].
T236 3995-4221 Sentence denotes In addition to the active site, it has been reported that the flexible darunavir binds to another site on the surface of the enzyme, which accounts for its resilience against potential mutations in the targeted protease [103].
T237 4222-4264 Sentence denotes Darunavir was approved in 2015 by the U.S.
T238 4265-4351 Sentence denotes FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat.
T239 4352-4539 Sentence denotes Although structurally similar to ritonavir, cobicistat lacks antiviral activity due to the lack of the central phenyl-propanol moiety, a key structural feature of HIV protease inhibitors.
T240 4540-4635 Sentence denotes Darunavir/cobicistat is under clinical investigation for the treatment of SARS-CoV-2 infection.
T241 4636-4791 Sentence denotes This is potentially attributed to darunavir ability to in vitro inhibit SARS-CoV-2 in Vero E6 cells, albeit at high concentrations (EC50 = 46.41 µM) [104].
T242 4792-4896 Sentence denotes Mechanistically, this could be because darunavir potentially inhibits 3CLpro and/or PLpro of SARS-CoV-2.
T243 4897-4965 Sentence denotes The two enzymes are important for the viral glycoprotein processing.
T244 4966-5127 Sentence denotes However, in another in vitro study, darunavir/cobicistat demonstrated no activity against SARS-CoV-2 at clinically relevant concentrations in Caco-2 cells [105].
T245 5128-5284 Sentence denotes Furthermore, the results from a randomized controlled trial in China showed that darunavir/cobicistat was not effective in treating COVID-19 patients [106].
T246 5285-5582 Sentence denotes Regardless, darunavir is being tried in about three trials in combination with cobicistat (NCT04252274; n = 30), ritonavir/hydroxychloroquine (NCT04435587; n = 80), ritonavir/oseltamivir, ritonavir/oseltamivir/hydroxychloroquine, or ritonavir/favipiravir/hydroxychloroquine (NCT04303299; n = 320).
T247 5583-5664 Sentence denotes TMC310911 (also known as ASC-09) (Figure 6) is structurally similar to darunavir.
T248 5665-5751 Sentence denotes It is HIV-1 aspartate protease competitive inhibitor with improved antiviral activity.
T249 5752-5946 Sentence denotes TMC310911 has potent activity against the wild-type HIV-1 and against an extended spectrum of recombinant HIV-1 clinical isolates, including multiple protease inhibitors-resistant strains [107].
T250 5947-6035 Sentence denotes Similar to darunavir, it was evaluated with the pharmacokinetic booster ritonavir [108].
T251 6036-6135 Sentence denotes Currently, it is being tested in two clinical trials in China in patients infected with SARS-CoV-2.
T252 6136-6245 Sentence denotes It is being tested in combination with ritonavir (NCT04261907; n = 160) or oseltamivir (NCT04261270; n = 60).
T253 6246-6412 Sentence denotes In a recent computational exercise, TMC-310911 was reported as a potential inhibitor of Mpro of SARS-CoV-2 [66], yet this potential is to be experimentally confirmed.
T254 6414-6418 Sentence denotes 3.3.
T255 6419-6439 Sentence denotes Atazanavir (Reyataz)
T256 6440-6550 Sentence denotes Atazanavir (Figure 6) is another antiretroviral drug that competitively inhibits the HIV-1 aspartate protease.
T257 6551-6594 Sentence denotes Atazanavir was approved in 2003 by the U.S.
T258 6595-6741 Sentence denotes FDA and usually prescribed in combination with the pharmacokinetic booster cobicistat (combination is being marketed under the name Evotaz; 2015).
T259 6742-7004 Sentence denotes Currently, it is being evaluated alone (NCT04468087; n = 189) or in combination with NA-831 (neuroprotective agent; traneurocin) or dexamethasone for the treatment of COVID-19 infection (NCT04452565; n = 525) or with nitazoxanide/ritonavir (NCT04459286; n = 98).
T260 7005-7192 Sentence denotes The drug alone or in combination with ritonavir demonstrated in vitro activity against SARS-CoV-2 in Vero E6 cells, human epithelial pulmonary cells (A549), and human monocytes [109,110].
T261 7193-7263 Sentence denotes In these studies, atazanavir has been identified as inhibitor of Mpro.
T262 7264-7389 Sentence denotes The drug and its combination have been projected to be 10-fold more potent than lopinavir and its combination with ritonavir.
T263 7390-7475 Sentence denotes The drug also inhibited the virus-induced enhancement of IL-6 and TNF-α levels [109].
T264 7476-7632 Sentence denotes In a separate computational study, atazanavir was reported as a potential inhibitor of SARS-CoV-2 helicase, a viral enzyme that unwinds nucleic acids [111].
T265 7634-7638 Sentence denotes 3.4.
T266 7639-7659 Sentence denotes Danoprevir/Ritonavir
T267 7660-7772 Sentence denotes Danoprevir (Ganovo) is an orally bioavailable 15-membered macrocyclic peptidomimetic antiviral drug (Figure S4).
T268 7773-7855 Sentence denotes It is an inhibitor of NS3/4A HCV protease, an important processing enzyme complex.
T269 7856-7917 Sentence denotes It inhibits the protease with an IC50 value of 0.29 nM [112].
T270 7918-7981 Sentence denotes It was approved in China in 2018 to treat chronic HCV patients.
T271 7982-8065 Sentence denotes At higher concentrations, it also appears to inhibit the aspartate protease of HIV.
T272 8066-8205 Sentence denotes The NS3/4A protease of HCV is claimed to share a certain level of structural and/or functional similarity to the protease(s) of SARS-CoV-2.
T273 8206-8317 Sentence denotes Thus, HCV protease inhibitors, including danoprevir, have been proposed as potential therapeutics for COVID-19.
T274 8318-8614 Sentence denotes This has also been supported by computational work which indicated that HCV protease inhibitors have high binding affinity to 3CLpro of SARS-CoV-2 [113] and by in vitro and clinical studies which showed that patients with SARS-CoV or MERS-CoV may benefit from HCV protease inhibitors [88,90,114].
T275 8615-8817 Sentence denotes Currently, danoprevir in combination with ritonavir, is being evaluated in two clinical trials (NCT04345276; n = 10) and (with nebulized INF; NCT04291729; n = 11) for the treatment of COVID-19 patients.
T276 8818-8994 Sentence denotes As mentioned earlier, ritonavir is an antiviral and pharmacokinetic booster that extends the systemic exposure of patients to potential therapeutic concentration of danoprevir.
T277 8995-9193 Sentence denotes In fact, a recent clinical study results under review has indicated that danoprevir/ritonavir combination alleviated the symptoms in COVID-patients and accelerated their recovery in 4–12 days [115].
T278 9195-9199 Sentence denotes 3.5.
T279 9200-9221 Sentence denotes Maraviroc (Selzentry)
T280 9222-9507 Sentence denotes It is a small, synthetic, azabicyclic molecule (Figure S4) that exhibits antiretroviral activity by blocking the interaction between HIV-1 glycoprotein 120 and chemokine receptor 5 (C-C motif receptor 5), on human CD4-presenting cells, that is necessary for HIV-1 to enter cells [116].
T281 9508-9541 Sentence denotes The drug was approved by the U.S.
T282 9542-9585 Sentence denotes FDA in 2007 as an oral treatment for HIV-1.
T283 9586-9716 Sentence denotes The drug is currently being evaluated in three clinical trials (NCT04441385, NCT04435522, and NCT04475991) for COVID-19 treatment.
T284 9717-9802 Sentence denotes Recently, it was shown that maraviroc may act as a potential inhibitor of Mpro [117].
T285 9803-10016 Sentence denotes However, it appears that it is more realistic to assume that the drug is a viral entry inhibitor and potentially acts by blocking the interaction between the viral spike S protein and the host ACE2 receptor [118].