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1.
Thorac Cancer ; 13(10): 1463-1470, 2022 05.
Article in English | MEDLINE | ID: covidwho-1846156

ABSTRACT

BACKGROUND: The aim of this prospective, pilot, single-arm phase II trial was to evaluate the safety and efficacy of anlotinib combined with etoposide and platinum-based regimens in the first-line treatment of extensive-stage small cell lung cancer (ES-SCLC). METHODS: This phase II study was conducted at Fudan University Shanghai Cancer Center between December 2018 and December 2020. All patients received standard chemotherapy (etoposide plus cisplatin/carboplatin) consisting of four courses and anlotinib at 12 mg once per day for 2 weeks followed by a one-week rest. Anlotinib administration was continued until disease progression, intolerable adverse events (AEs) or patient withdrawal from the study. The primary outcome measure was progression-free survival (PFS). The secondary outcome measures were overall survival (OS), objective control rate (ORR), disease control rate (DCR) and AEs. RESULTS: Thirty-seven patients were included in this study, and 30 patients were eligible for efficacy analysis. ORR and DCR were 90.0% and 96.7%, respectively. The estimated PFS and OS were 6.0 months (95% CI: 1.1-11.9 months) and 14.0 months (95% CI: 8.6-19.4 months), respectively. No unexpected adverse effects were reported. Hypertension (20/37, 54.1%), anemia (16/37, 43.2%), alopecia (15/37, 40.5%), elevated transaminases (9/37, 24.3%) and alkaline phosphatase (9/37, 24.3%) were the most commonly reported AEs. Thirteen patients (35.1%) reported grade 3-5 AEs. No treatment-related deaths occurred during this study. CONCLUSION: The addition of anlotinib to standard etoposide/platinum chemotherapy achieved encouraging PFS and OS in previously untreated ES-SCLC patients, with an acceptable tolerability profile and no new safety signals observed.


Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carboplatin , China , Etoposide , Humans , Indoles , Platinum/pharmacology , Platinum/therapeutic use , Prospective Studies , Quinolines
2.
Commun Biol ; 5(1): 391, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1815611

ABSTRACT

Protease inhibitors are among the most powerful antiviral drugs. However, for SARS-CoV-2 only a small number of protease inhibitors have been identified thus far and there is still a great need for assays that efficiently report protease activity and inhibition in living cells. Here, we engineer a safe VSV-based system to report both gain- and loss-of-function of coronavirus main protease (Mpro/3CLpro/Nsp5) activity in living cells. We use SARS-CoV-2 3CLpro in this system to confirm susceptibility to known inhibitors (boceprevir, GC376, PF-00835231, and PF-07321332/nirmatrelvir) and reevaluate other reported inhibitors (baicalein, ebselen, carmofur, ethacridine, ivermectin, masitinib, darunavir, and atazanavir). Moreover, we show that the system can be adapted to report both the function and the chemical inhibition of proteases from different coronavirus species as well as from distantly related viruses. Together with the fact that live cell assays also reflect compound permeability and toxicity, we anticipate that this system will be useful for both identification and optimization of additional coronavirus protease inhibitors.


Subject(s)
COVID-19 , Cysteine Endopeptidases , Humans , Indoles , Lactams , Leucine , Nitriles , Peptide Hydrolases , Proline , Protease Inhibitors/pharmacology , Pyrrolidinones , SARS-CoV-2 , Viral Proteins/chemistry
3.
Clin Pharmacol Ther ; 111(6): 1324-1333, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1802136

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies, including elexacaftor-tezacaftor-ivacaftor, are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of coronavirus disease 2019 (COVID-19) with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDIs). However, the population with CF is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of elexacaftor-tezacaftor-ivacaftor was evaluated using a physiologically-based pharmacokinetic modeling approach. Modeling was performed incorporating physiological information and drug-dependent parameters of elexacaftor-tezacaftor-ivacaftor to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on the pharmacokinetics of elexacaftor-tezacaftor-ivacaftor. The elexacaftor-tezacaftor-ivacaftor models were verified using independent clinical pharmacokinetic and DDI data of elexacaftor-tezacaftor-ivacaftor with a range of CYP3A modulators. When ritonavir was administered on Days 1 through 5, the predicted area under the curve (AUC) ratio of ivacaftor (the most sensitive CYP3A substrate) on Day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of elexacaftor-tezacaftor-ivacaftor should be reduced when coadministered with nirmatrelvir-ritonavir to elexacaftor 200 mg-tezacaftor 100 mg-ivacaftor 150 mg on Days 1 and 5, with delayed resumption of full-dose elexacaftor-tezacaftor-ivacaftor on Day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of elexacaftor-tezacaftor-ivacaftor administered concomitantly with nirmatrelvir-ritonavir in people with CF that will likely decrease the impact of the drug interaction.


Subject(s)
COVID-19 , Cystic Fibrosis , Aminophenols/pharmacology , Benzodioxoles/pharmacology , COVID-19/drug therapy , Chloride Channel Agonists/therapeutic use , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator , Cytochrome P-450 CYP3A/metabolism , Drug Combinations , Drug Interactions , Humans , Indoles/pharmacology , Lactams/pharmacokinetics , Leucine/pharmacokinetics , Mutation , Nitriles/pharmacokinetics , Proline/pharmacokinetics , Pyrazoles/pharmacology , Pyridines/pharmacology , Pyrrolidines , Quinolines/pharmacology , Quinolones , Ritonavir/pharmacokinetics
4.
Biochem Biophys Res Commun ; 604: 76-82, 2022 05 14.
Article in English | MEDLINE | ID: covidwho-1797136

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and seriously threatened public health and safety. Despite COVID-19 vaccines being readily popularized worldwide, targeted therapeutic agents for the treatment of this disease remain very limited. Here, we studied the inhibitory activity of the scutellarein and its methylated derivatives against SARS-CoV-2 main protease (Mpro) by the fluorescence resonance energy transfer (FRET) assay. Among all the methylated derivatives we studied, 4'-O-methylscutellarein exhibited the most promising enzyme inhibitory activity in vitro, with the half-maximal inhibitory concentration value (IC50) of 0.40 ± 0.03 µM. Additionally, the mechanism of action of the hits was further characterized through enzyme kinetic studies and molecular docking. Overall, our results implied that 4'-O-methylscutellarein could be a primary lead compound with clinical potential for the development of inhibitors against the SARS-CoV-2 Mpro.


Subject(s)
Alkaloids , Coronavirus 3C Proteases , Indoles , SARS-CoV-2 , Viral Protease Inhibitors , Alkaloids/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Humans , Indoles/pharmacology , Kinetics , Molecular Docking Simulation , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Viral Protease Inhibitors/pharmacology
5.
J Med Virol ; 94(4): 1513-1522, 2022 04.
Article in English | MEDLINE | ID: covidwho-1718397

ABSTRACT

OBJECTIVES: To systematically evaluate the efficacy and safety of arbidol and lopinavir/ritonavir (LPV/r) in the treatment of coronavirus disease 2019 (COVID-19) using a meta-analysis method. METHODS: The China Knowledge Network, VIP database, WanFang database PubMed database, Embase database, and Cochrane Library were searched for a collection of comparative studies on arbidol and lopinavir/ritonavir in the treatment of COVID-19. Meta-analysis was used to evaluate the efficacy and safety of Arbidol and lopinavir/ritonavir in the treatment of COVID-19. RESULTS: The results of the systematic review indicated that Arbidol had a higher positive-to-negative conversion rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleic acid on Day 7 (p = 0.03), a higher positive-to-negative conversion rate of SARS-CoV-2 nucleic acid on Day 14 (p = 0.006), a higher improvement rate of chest computed tomography on Day 14 (p = 0.02), a lower incidence of adverse reactions (p = 0.002) and lower rate of mortality (p = 0.007). There was no difference in the rate of cough disappearance on Day 14 (p = 0.24) or the rate of severe/critical illness (p = 0.07) between the two groups. CONCLUSIONS: Arbidol may be superior to lopinavir/ritonavir in the treatment of COVID-19. However, due to the small number of included studies and the number of patients, high-quality multicenter large-sample randomized double-blind controlled trials are still needed for verification.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Indoles/therapeutic use , Lopinavir/therapeutic use , Ritonavir/therapeutic use , Sulfides/therapeutic use , COVID-19/mortality , Drug Combinations , Humans , Indoles/adverse effects , Lopinavir/adverse effects , Ritonavir/adverse effects , SARS-CoV-2/drug effects , Sulfides/adverse effects , Treatment Outcome
6.
J Med Virol ; 94(4): 1745-1747, 2022 04.
Article in English | MEDLINE | ID: covidwho-1718409

ABSTRACT

Methylprednisolone (MP) is usually used to reduce inflammation reaction and tissue damage, which may have a beneficial treatment effect on coronavirus disease 2019 (COVID-19). However, we present the case of a child who manifests significant bradycardia with the use of just low dose MP on the premise of the long-term use of arbidol. Arbidol can affect the activity of CYP3A4, which is also a key metabolic enzyme of MP by competitive inhibition, and which is easy to aggravate the side effects of MP. Therefore, more attention should be paid to bradycardia occurrence in the patient with COVID-19 when MP is considered in COVID-19.


Subject(s)
Anti-Inflammatory Agents/adverse effects , Bradycardia/chemically induced , COVID-19/drug therapy , Methylprednisolone/adverse effects , Antiviral Agents/adverse effects , COVID-19/diagnosis , Child , Drug Therapy, Combination/adverse effects , Humans , Indoles/adverse effects , Male , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Sulfides/adverse effects
8.
Rev Esp Quimioter ; 35(3): 236-240, 2022 Jun.
Article in Spanish | MEDLINE | ID: covidwho-1698934

ABSTRACT

All coronavirus, including SARS-CoV-2, encode two proteases needed for the processing of PP1A and PP1AB polyproteins. The main protease 3CL (chemotripsine-like) gives rise to the formation of NSP11/16 proteins. The 3CL protease has been constituted as one of the possible therapeutic targets for the development of antiviral drugs against SARS-COV-2 due to its highly conserved sequence and structure among all coronaviruses. During the SARS-COV-1 pandemic, a hydroxymethyl ketone derivative (PF-00835231) was identified with an intense inhibitory activity against the 3CL protease. Subsequent chemical modifications gave rise to derivative PF-07321332 (nirmatrelvir) which has shown a high antiviral efficacy against SARS-COV-2. The company's data indicate that it is capable of reducing 89% the risk of hospitalization and death of patients infected with hardly adverse effects. Its effectiveness improves if it is administered orally in the first 24-48 hours and the duration of treatment has been established between 3-5 days. The commercial form has been associated with the antiviral ritonavir that has shown the metabolism of nirmatrelvir, lengthening its average life. This antiviral would be effective against current and future viral variants, since 3CL is not modified in them. The FDA approved this antiviral in November 2021 and EMA is in the final evaluation phase.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Combinations , Humans , Indoles , Lactams , Leucine , Nitriles , Peptide Hydrolases/metabolism , Proline , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Pyrrolidinones , Ritonavir/therapeutic use
9.
J Virol ; 95(24): e0139921, 2021 11 23.
Article in English | MEDLINE | ID: covidwho-1691426

ABSTRACT

Targeting host factors is a promising strategy to develop broad-spectrum antiviral drugs. Drugs targeting anti-apoptotic Bcl-2 family proteins that were originally developed as tumor suppressors have been reported to inhibit multiplication of different types of viruses. However, the mechanisms whereby Bcl-2 inhibitors exert their antiviral activity remain poorly understood. In this study, we have investigated the mechanisms by which obatoclax (OLX) and ABT-737 Bcl-2 inhibitors exhibited a potent antiviral activity against the mammarenavirus lymphocytic choriomeningitis virus (LCMV). OLX and ABT-737 potent anti-LCMV activity was not associated with their proapoptotic properties but rather with their ability to induce cell arrest at the G0/G1 phase. OLX- and ABT-737-mediated inhibition of Bcl-2 correlated with reduced expression levels of thymidine kinase 1 (TK1), cyclin A2 (CCNA2), and cyclin B1 (CCNB1) cell cycle regulators. In addition, small interfering RNA (siRNA)-mediated knockdown of TK1, CCNA2, and CCNB1 resulted in reduced levels of LCMV multiplication. The antiviral activity exerted by Bcl-2 inhibitors correlated with reduced levels of viral RNA synthesis at early times of infection. Importantly, ABT-737 exhibited moderate efficacy in a mouse model of LCMV infection, and Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals. IMPORTANCE Antiapoptotic Bcl-2 inhibitors have been shown to exert potent antiviral activities against various types of viruses via mechanisms that are currently poorly understood. This study has revealed that Bcl-2 inhibitors' mediation of cell cycle arrest at the G0/G1 phase, rather than their proapoptotic activity, plays a critical role in blocking mammarenavirus multiplication in cultured cells. In addition, we show that Bcl-2 inhibitor ABT-737 exhibited moderate antimammarenavirus activity in vivo and that Bcl-2 inhibitors displayed broad-spectrum antiviral activities against different mammarenaviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our results suggest that Bcl-2 inhibitors, actively being explored as anticancer therapeutics, might be repositioned as broad-spectrum antivirals.


Subject(s)
Apoptosis , Arenaviridae/drug effects , COVID-19/drug therapy , Proto-Oncogene Proteins c-bcl-2/metabolism , A549 Cells , Animals , Antiviral Agents/pharmacology , Apoptosis Regulatory Proteins/pharmacology , Biphenyl Compounds/pharmacology , COVID-19/virology , Cell Cycle , Cell Cycle Checkpoints/drug effects , Cells, Cultured/drug effects , Cells, Cultured/virology , Chlorocebus aethiops , Cyclin A2/biosynthesis , Cyclin B1/biosynthesis , G1 Phase , Humans , Indoles/pharmacology , Mice , Mice, Inbred C57BL , Nitrophenols/pharmacology , Piperazines/pharmacology , Pyrroles/pharmacology , Resting Phase, Cell Cycle , SARS-CoV-2 , Sulfonamides/pharmacology , Thymidine Kinase/biosynthesis , Vero Cells
10.
Med Sci Monit ; 28: e934102, 2022 Jan 25.
Article in English | MEDLINE | ID: covidwho-1651076

ABSTRACT

BACKGROUND Heat-clearing and detoxifying herbs (HDHs) play an important role in the prevention and treatment of coronavirus infection. However, their mechanism of action needs further study. This study aimed to explore the anti-coronavirus basis and mechanism of HDHs. MATERIAL AND METHODS Database mining was performed on 7 HDHs. Core ingredients and targets were screened according to ADME rules combined with Neighborhood, Co-occurrence, Co-expression, and other algorithms. GO enrichment and KEGG pathway analyses were performed using the R language. Finally, high-throughput molecular docking was used for verification. RESULTS HDHs mainly acts on NOS3, EGFR, IL-6, MAPK8, PTGS2, MAPK14, NFKB1, and CASP3 through quercetin, luteolin, wogonin, indirubin alkaloids, ß-sitosterol, and isolariciresinol. These targets are mainly involved in the regulation of biological processes such as inflammation, activation of MAPK activity, and positive regulation of NF-kappaB transcription factor activity. Pathway analysis further revealed that the pathways regulated by these targets mainly include: signaling pathways related to viral and bacterial infections such as tuberculosis, influenza A, Ras signaling pathways; inflammation-related pathways such as the TLR, TNF, MAPK, and HIF-1 signaling pathways; and immune-related pathways such as NOD receptor signaling pathways. These pathways play a synergistic role in inhibiting lung inflammation and regulating immunity and antiviral activity. CONCLUSIONS HDHs play a role in the treatment of coronavirus infection by regulating the body's immunity, fighting inflammation, and antiviral activities, suggesting a molecular basis and new strategies for the treatment of COVID-19 and a foundation for the screening of new antiviral drugs.


Subject(s)
COVID-19/drug therapy , Coronavirus/drug effects , Drugs, Chinese Herbal/pharmacology , SARS-CoV-2/drug effects , Alkaloids/chemistry , Alkaloids/pharmacology , Caspase 3/drug effects , Caspase 3/genetics , Coronavirus/metabolism , Coronavirus Infections/drug therapy , Cyclooxygenase 2/drug effects , Cyclooxygenase 2/genetics , Databases, Pharmaceutical , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Flavanones/chemistry , Flavanones/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Interleukin-6/genetics , Lignin/chemistry , Lignin/pharmacology , Luteolin/chemistry , Luteolin/pharmacology , Mitogen-Activated Protein Kinase 14/drug effects , Mitogen-Activated Protein Kinase 14/genetics , Mitogen-Activated Protein Kinase 8/drug effects , Mitogen-Activated Protein Kinase 8/genetics , Molecular Docking Simulation , NF-kappa B p50 Subunit/drug effects , NF-kappa B p50 Subunit/genetics , Naphthols/chemistry , Naphthols/pharmacology , Nitric Oxide Synthase Type III/drug effects , Nitric Oxide Synthase Type III/genetics , Protein Interaction Maps , Quercetin/chemistry , Quercetin/pharmacology , SARS-CoV-2/metabolism , Signal Transduction , Sitosterols/chemistry , Sitosterols/pharmacology , Transcriptome/drug effects , Transcriptome/genetics
11.
Emerg Microbes Infect ; 11(1): 483-497, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-1606402

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a promising approach. We assessed the compounds that affect the endosomal acidic environment by applying human angiotensin-converting enzyme 2 (hACE2)- expressing cells infected with a SARS-CoV-2 spike (S) protein-pseudotyped HIV reporter virus and identified that obatoclax resulted in the strongest inhibition of S protein-mediated virus entry. The potent antiviral activity of obatoclax at nanomolar concentrations was confirmed in different human lung and intestinal cells infected with the SARS-CoV-2 pseudotype system as well as clinical virus isolates. Furthermore, we uncovered that obatoclax executes a double-strike against SARS-CoV-2. It prevented SARS-CoV-2 entry by blocking endocytosis of virions through diminished endosomal acidification and the corresponding inhibition of the enzymatic activity of the endosomal cysteine protease cathepsin L. Additionally, obatoclax impaired the SARS-CoV-2 S-mediated membrane fusion by targeting the MCL-1 protein and reducing furin protease activity. In accordance with these overarching mechanisms, obatoclax blocked the virus entry mediated by different S proteins derived from several SARS-CoV-2 variants of concern such as, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Taken together, our results identified obatoclax as a novel effective antiviral compound that keeps SARS-CoV-2 at bay by blocking both endocytosis and membrane fusion. Our data suggested that obatoclax should be further explored as a clinical drug for the treatment of COVID-19.


Subject(s)
Cathepsins/metabolism , Furin/metabolism , Indoles/pharmacology , Pyrroles/pharmacology , SARS-CoV-2 , Virus Internalization/drug effects , COVID-19 , Humans , Hydrogen-Ion Concentration , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus
12.
Adv Respir Med ; 89(6): 589-596, 2021.
Article in English | MEDLINE | ID: covidwho-1595790

ABSTRACT

The current COVID-19 pandemic has spread like wildfire worldwide and has affected millions of people. The novel corona virus mainly affects the lungs leading to life threatening disease like acute respiratory distress syndrome (ARDS). The aftermath of the disease in form of pulmonary fibrosis is upcoming cause of further increase in morbidity and mortality. Nintedanib is an oral antifibrotics with proven role in idiopathic pulmonary fibrosis, however its use in COVID-19 related pulmonary fibrosis has not been studied. We report our early experience of use of nintedanib in COVID-19 related pulmonary fibrosis.


Subject(s)
COVID-19/drug therapy , Idiopathic Pulmonary Fibrosis/drug therapy , Indoles/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory System Agents/therapeutic use , COVID-19/diet therapy , Humans , Idiopathic Pulmonary Fibrosis/etiology , Respiratory Distress Syndrome/etiology
13.
Nat Commun ; 12(1): 7327, 2021 12 16.
Article in English | MEDLINE | ID: covidwho-1585856

ABSTRACT

The global disruption caused by the 2020 coronavirus pandemic stressed the supply chain of many products, including pharmaceuticals. Multiple drug repurposing studies for COVID-19 are now underway. If a winning therapeutic emerges, it is unlikely that the existing inventory of the medicine, or even the chemical raw materials needed to synthesize it, will be available in the quantities required. Here, we utilize retrosynthetic software to arrive at alternate chemical supply chains for the antiviral drug umifenovir, as well as eleven other antiviral and anti-inflammatory drugs. We have experimentally validated four routes to umifenovir and one route to bromhexine. In one route to umifenovir the software invokes conversion of six C-H bonds into C-C bonds or functional groups. The strategy we apply of excluding known starting materials from search results can be used to identify distinct starting materials, for instance to relieve stress on existing supply chains.


Subject(s)
Antiviral Agents/chemistry , COVID-19/drug therapy , Indoles/chemistry , Software , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , Drug Repositioning , Humans , Indoles/therapeutic use , SARS-CoV-2/drug effects
14.
Molecules ; 26(24)2021 Dec 09.
Article in English | MEDLINE | ID: covidwho-1572567

ABSTRACT

COVID-19 is the name of the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection that occurred in 2019. The virus-host-specific interactions, molecular targets on host cell deaths, and the involved signaling are crucial issues, which become potential targets for treatment. Spike protein, angiotensin-converting enzyme 2 (ACE2), cathepsin L-cysteine peptidase, transmembrane protease serine 2 (TMPRSS2), nonstructural protein 1 (Nsp1), open reading frame 7a (ORF7a), viral main protease (3C-like protease (3CLpro) or Mpro), RNA dependent RNA polymerase (RdRp) (Nsp12), non-structural protein 13 (Nsp13) helicase, and papain-like proteinase (PLpro) are molecules associated with SARS-CoV infection and propagation. SARS-CoV-2 can induce host cell death via five kinds of regulated cell death, i.e., apoptosis, necroptosis, pyroptosis, autophagy, and PANoptosis. The mechanisms of these cell deaths are well established and can be disrupted by synthetic small molecules or natural products. There are a variety of compounds proven to play roles in the cell death inhibition, such as pan-caspase inhibitor (z-VAD-fmk) for apoptosis, necrostatin-1 for necroptosis, MCC950, a potent and specific inhibitor of the NLRP3 inflammasome in pyroptosis, and chloroquine/hydroxychloroquine, which can mitigate the corresponding cell death pathways. However, NF-κB signaling is another critical anti-apoptotic or survival route mediated by SARS-CoV-2. Such signaling promotes viral survival, proliferation, and inflammation by inducing the expression of apoptosis inhibitors such as Bcl-2 and XIAP, as well as cytokines, e.g., TNF. As a result, tiny natural compounds functioning as proteasome inhibitors such as celastrol and curcumin can be used to modify NF-κB signaling, providing a responsible method for treating SARS-CoV-2-infected patients. The natural constituents that aid in inhibiting viral infection, progression, and amplification of coronaviruses are also emphasized, which are in the groups of alkaloids, flavonoids, terpenoids, diarylheptanoids, and anthraquinones. Natural constituents derived from medicinal herbs have anti-inflammatory and antiviral properties, as well as inhibitory effects, on the viral life cycle, including viral entry, replication, assembly, and release of COVID-19 virions. The phytochemicals contain a high potential for COVID-19 treatment. As a result, SARS-CoV-2-infected cell death processes and signaling might be of high efficacy for therapeutic targeting effects and yielding encouraging outcomes.


Subject(s)
COVID-19/drug therapy , Cell Death/drug effects , Drug Discovery/methods , Molecular Targeted Therapy/methods , SARS-CoV-2/drug effects , Amino Acid Chloromethyl Ketones/pharmacology , Antiviral Agents/pharmacology , Apoptosis/drug effects , Furans/pharmacology , Humans , Hydroxychloroquine/pharmacology , Imidazoles/pharmacology , Indenes/pharmacology , Indoles/pharmacology , Necroptosis/drug effects , Phytochemicals/pharmacology , Pyroptosis/drug effects , SARS-CoV-2/metabolism , Signal Transduction/drug effects , Sulfonamides/pharmacology , Viral Proteins/antagonists & inhibitors
15.
J Chem Inf Model ; 61(12): 5906-5922, 2021 12 27.
Article in English | MEDLINE | ID: covidwho-1569200

ABSTRACT

Umifenovir (Arbidol) has been reported to exhibit some degree of efficacy in multiple clinical trials for the treatment of COVID-19 as a monotherapy. It has also demonstrated synergistic inhibition of SARS-CoV-2 with other direct-acting antivirals such as Remdesivir. A computational approach was used to identify the most favorable binding site to the SARS-CoV-2 Spike S2 segment and to perform virtual screening. Compounds selected from modeling were evaluated in a live SARS-CoV-2 infection assay. An Arbidol (ARB) derivative with substitutions at both the C-4 and C-6 positions was found to exhibit a modest improvement in activity and solubility properties in comparison to ARB. However, all of the derivatives were found to only be partial inhibitors, rather than full inhibitors in a virus-induced cytopathic effect-based assay. The binding mode is also corroborated by parallel modeling of a series of oleanolic acid trisaccharide saponin fusion inhibitors shown to bind to the S2 segment. Recently determined experimental structures of the Spike protein allowed atomic resolution modeling of fusion inhibitor binding as a function of pH, and the implications for the molecular mechanism of direct-acting fusion inhibitors targeting the S2 segment are discussed.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Antiviral Agents/pharmacology , Humans , Indoles , SARS-CoV-2 , Spike Glycoprotein, Coronavirus , Structure-Activity Relationship , Virus Internalization
16.
Zhonghua Nei Ke Za Zhi ; 59(8): 605-609, 2020 Aug 01.
Article in Chinese | MEDLINE | ID: covidwho-1556260

ABSTRACT

Objective: To evaluate the efficacy and safety of lopinavir/ritonavir (LPV/r) and arbidol in treating patients with coronavirus disease 2019 (COVID-19) in the real world. Methods: The clinical data of 178 patients diagnosed with COVID-19 admitted to Guangzhou Eighth People's Hospital from January 20 to February 10, 2020 were retrospectively analyzed. According to patient's antiviral treatment regimens, 178 patients were divided into 4 groups including LPV/r group (59 patients), arbidol group (36 patients), LPV/r plus arbidol combination group (25 patients) and the supportive care group without any antiviral treatment (58 patients). The primary end point was the negative conversion time of nucleic acid of 2019 novel coronavirus (2019-nCoV) by pharyngeal swab. Results: The baseline parameters of 4 groups before treatment was comparable. The negative conversion time of viral nucleic acid was (10.20±3.49), (10.11±4.68), (10.86±4.74), (8.44±3.51) days in LPV/r group, arbidol group, combination group, and supportive care group respectively (F=2.556, P=0.058). There was also no significant difference in negative conversion rate of 2019-nCoV nucleic acid, the improvement of clinical symptoms, and the improvement of pulmonary infections by CT scan (P>0.05). However, a statistically significant difference was found in the changing rates from mild/moderate to severe/critical type at day 7 (χ(2)=9.311, P=0.017), which were 24%(6/25) in combination group, 16.7%(6/36) in arbidol group, 5.4%(3/56) in LPV/r group and 5.2%(3/58) in supportive care group. Moreover, the incidence of adverse reactions in three antiviral groups was significantly higher than that in supportive care group (χ(2)=14.875, P=0.002). Conclusions: Antiviral treatment including LPV/r or arbidol or combination does not shorten the negative conversion time of 2019-nCoV nucleic acid nor improve clinical symptoms. Moreover, these antiviral drugs cause more adverse reactions which should be paid careful attention during the treatment.


Subject(s)
COVID-19 , HIV Infections , COVID-19/drug therapy , HIV Infections/drug therapy , Humans , Indoles , Lopinavir/adverse effects , Retrospective Studies , Ritonavir/adverse effects , SARS-CoV-2
17.
Expert Opin Investig Drugs ; 30(12): 1183-1195, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1541410

ABSTRACT

INTRODUCTION: Lung injury in severe COVID-19 pneumonia can rapidly evolve to established pulmonary fibrosis, with prognostic implications in the acute phase of the disease and long-lasting impact on the quality of life of COVID-19 survivors. This is an emerging medical need, and it has been hypothesized that antifibrotic treatments could have a role in ameliorating the fibrotic process in the lungs of these patients. AREAS COVERED: The safety and efficacy of available antifibrotic drugs (nintedanib and pirfenidone) and novel promising agents are being assessed in several ongoing clinical trials that were performed either in critically ill patients admitted to intensive care, or in discharged patients presenting fibrotic sequalae from COVID-19. Literature search was performed using Medline and Clinicaltrials.org databases (2001-2021). EXPERT OPINION: Despite the strong rationale support the use of antifibrotic therapies in COVID-related fibrosis, there are several uncertainties regarding the timing for their introduction and the real risks/benefits ratio of antifibrotic treatment in the acute and the chronic phases of the disease. The findings of ongoing clinical trials and the long-term observation of longitudinal cohorts will eventually clarify the best management approach for these patients.


Subject(s)
/therapeutic use , COVID-19/complications , Pulmonary Fibrosis/drug therapy , Pulmonary Fibrosis/etiology , Animals , Critical Illness , Humans , Indoles/therapeutic use , Pyridones
18.
SAR QSAR Environ Res ; 32(12): 963-983, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1532255

ABSTRACT

The coronavirus helicase is an essential enzyme required for viral replication/transcription pathways. Structural studies revealed a sulphate moiety that interacts with key residues within the nucleotide-binding site of the helicase. Compounds with a sulphoxide or a sulphone moiety could interfere with these interactions and consequently inhibit the enzyme. The molecular operating environment (MOE) was used to dock 189 sulphoxide and sulphone-containing FDA-approved compounds to the nucleotide-binding site. Zafirlukast, a leukotriene receptor antagonist used to treat chronic asthma, achieved the lowest docking score at -8.75 kcals/mol. The inhibitory effect of the compounds on the SARS-CoV-2 helicase dsDNA unwinding activity was tested by a FRET-based assay. Zafirlukast was the only compound to inhibit the enzyme (IC50 = 16.3 µM). The treatment of Vero E6 cells with 25 µM zafirlukast prior to SARS-CoV-2 infection decreased the cytopathic effects of SARS-CoV-2 significantly. These results suggest that zafirlukast alleviates SARS-CoV-2 pathogenicity by inhibiting the viral helicase and impairing the viral replication/transcription pathway. Zafirlukast could be clinically developed as a new antiviral treatment for SARS-CoV-2 and other coronavirus diseases. This discovery is based on molecular modelling, in vitro inhibition of the SARS-CoV helicase activity and cell-based SARS-CoV-2 viral replication.


Subject(s)
Antiviral Agents/pharmacology , DNA Helicases/antagonists & inhibitors , Indoles/pharmacology , Phenylcarbamates/pharmacology , SARS-CoV-2/drug effects , Sulfonamides/pharmacology , Animals , COVID-19/drug therapy , Chlorocebus aethiops , Fluorescence Resonance Energy Transfer , Quantitative Structure-Activity Relationship , SARS-CoV-2/enzymology , Vero Cells , Virus Replication/drug effects
19.
Theranostics ; 11(14): 7005-7017, 2021.
Article in English | MEDLINE | ID: covidwho-1524524

ABSTRACT

The tumor suppressor protein p53 remains in a wild type but inactive form in ~50% of all human cancers. Thus, activating it becomes an attractive approach for targeted cancer therapies. In this regard, our lab has previously discovered a small molecule, Inauhzin (INZ), as a potent p53 activator with no genotoxicity. Method: To improve its efficacy and bioavailability, here we employed nanoparticle encapsulation, making INZ-C, an analog of INZ, to nanoparticle-encapsulated INZ-C (n-INZ-C). Results: This approach significantly improved p53 activation and inhibition of lung and colorectal cancer cell growth by n-INZ-C in vitro and in vivo while it displayed a minimal effect on normal human Wi38 and mouse MEF cells. The improved activity was further corroborated with the enhanced cellular uptake observed in cancer cells and minimal cellular uptake observed in normal cells. In vivo pharmacokinetic evaluation of these nanoparticles showed that the nanoparticle encapsulation prolongates the half-life of INZ-C from 2.5 h to 5 h in mice. Conclusions: These results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Indoles/pharmacology , Lung Neoplasms/drug therapy , Nanoparticles/chemistry , Phenothiazines/pharmacology , Tumor Suppressor Protein p53/metabolism , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Biological Availability , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Humans , Indoles/chemistry , Indoles/pharmacokinetics , Indoles/therapeutic use , Mice , Mice, Inbred C57BL , Microscopy, Electron, Transmission , Nanoparticles/toxicity , Nanoparticles/ultrastructure , Phenothiazines/chemistry , Phenothiazines/pharmacokinetics , Phenothiazines/therapeutic use , Spectroscopy, Fourier Transform Infrared , Tumor Suppressor Protein p53/genetics , Xenograft Model Antitumor Assays
20.
ACS Chem Biol ; 16(12): 2845-2851, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1521690

ABSTRACT

Arbidol (ARB) is a broad-spectrum antiviral drug approved in Russia and China for the treatment of influenza. ARB was tested in patients as a drug candidate for the treatment at the early onset of COVID-19 caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite promising clinical results and multiple ongoing trials, preclinical data are lacking and the molecular mechanism of action of ARB against SARS-CoV-2 remains unknown. Here, we demonstrate that ARB binds to the spike viral fusion glycoprotein of the SARS-CoV-2 Wuhan strain as well as its more virulent variants from the United Kingdom (strain B.1.1.7) and South Africa (strain B.1.351). We pinpoint the ARB binding site on the S protein to the S2 membrane fusion domain and use an infection assay with Moloney murine leukemia virus (MLV) pseudoviruses (PVs) pseudotyped with the S proteins of the Wuhan strain and the new variants to show that this interaction is sufficient for the viral cell entry inhibition by ARB. Finally, our experiments reveal that the ARB interaction leads to a significant destabilization and eventual lysosomal degradation of the S protein in cells. Collectively, our results identify ARB as the first clinically approved small molecule drug binder of the SARS-CoV-2 S protein and place ARB among the more promising drug candidates for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Indoles/pharmacology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/metabolism , A549 Cells , Animals , Antiviral Agents/metabolism , Binding Sites , Chlorocebus aethiops , HEK293 Cells , Humans , Indoles/metabolism , Lysosomes/metabolism , Mutation , Protein Domains , Proteolysis/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vero Cells , Virus Internalization/drug effects
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