In vitro efficacy of artemisinin-based treatments against SARS-CoV-2.
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ABSTRACT:
SUBMITTER: Zhou Y
PROVIDER: S-EPMC8285423 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundTraditional medicines based on herbal extracts have been proposed as affordable treatments for patients suffering from coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Teas and drinks containing extracts of Artemisia annua and Artemisia afra have been widely used in Africa in efforts to prevent SARS-CoV-2 infection and fight COVID-19.MethodsThe plant extracts and Covid-Organics drink produced in Madagascar were tested for plaque reduction using both feline coronavirus and SARS-CoV-2 in vitro. Their cytotoxicities were also investigated.ResultsSeveral extracts as well as Covid-Organics inhibited SARS-CoV-2 and FCoV infection at concentrations that did not affect cell viability.ConclusionsSome plant extracts show inhibitory activity against FCoV and SARS-CoV-2. However, it remains unclear whether peak plasma concentrations in humans can reach levels needed to inhibit viral infection following consumption of teas or Covid-Organics. Clinical studies are required to evaluate the utility of these drinks for COVID-19 prevention or treatment of patients.
| S-EPMC8424155 | biostudies-literature
Project description:In 2019, coronavirus has made the third apparition in the form of SARS-CoV-2, a novel strain of coronavirus that is extremely pathogenic and it uses the same receptor as SARS-CoV, the angiotensin-converting enzyme 2 (ACE2). However, more than 182 vaccine candidates have been announced; and 12 vaccines have been approved for use, although, even vaccinated individuals are still vulnerable to infection. In this study, we investigated PHELA, recognized as an herbal combination of four exotic African medicinal plants namely; Clerodendrum glabrum E. Mey. Lamiaceae, Gladiolus dalenii van Geel, Rotheca myricoides (Hochst.) Steane & Mabb, and Senna occidentalis (L.) Link; as a candidate therapy for COVID-19. In vitro testing found that PHELA inhibited > 90% of SARS-CoV-2 and SARS-CoV infection at concentration levels of 0.005 mg/ml to 0.03 mg/ml and close to 100% of MERS-CoV infection at 0.1 mg/ml to 0.6 mg/ml. The in vitro average IC50 of PHELA on SARS-COV-2, SARS-CoV and MERS-COV were ~ 0.01 mg/ml. Secondly in silico docking studies of compounds identified in PHELA showed very strong binding energy interactions with the SARS-COV-2 proteins. Compound 5 showed the highest affinity for SARS-COV-2 protein compared to other compounds with the binding energy of - 6.8 kcal mol-1. Our data showed that PHELA has potential and could be developed as a COVID-19 therapeutic.
| S-EPMC9207029 | biostudies-literature
Project description:The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients. Virus-encoded proteases are considered potential drug targets. The human immunodeficiency virus protease inhibitors (lopinavir/ritonavir) has been recommended in the global Solidarity Trial in March launched by World Health Organization. However, there is currently no experimental evidence to support or against its clinical use. We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro, and discussed the possible inhibitory mechanism in silico. The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical. Among the four tested compounds, lopinavir showed the best inhibitory effect against the novel coronavirus infection. However, further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ritonavir could not reach effective concentration under standard dosing regimen [marketed as Kaletra®, contained lopinavir/ritonavir (200 mg/50 mg) tablets, recommended dosage is 400 mg/10 mg (2 tablets) twice daily]. This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration. Nevertheless, the structure-activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2.
| S-EPMC7481761 | biostudies-literature
Project description:Although interim results from several large placebo-controlled phase 3 trials demonstrated high vaccine efficacy (VE) against symptomatic COVID-19, it is unknown how effective the vaccines are in preventing people from becoming asymptomatically in- fected and potentially spreading the virus unwittingly. It is more difficult to evaluate VE against SARS-CoV-2 infection than against symptomatic COVID-19 because infection is not observed directly but rather is known to occur between two antibody or RT-PCR tests. Ad- ditional challenges arise as community transmission changes over time and as participants are vaccinated on different dates because of staggered enrollment of participants or crossover of placebo recipients to the vaccine arm before the end of the study. Here, we provide valid and efficient statistical methods for estimating potentially waning VE against SARS-CoV-2 infection with blood or nasal samples under time-varying community transmission, stag- gered enrollment, and blinded or unblinded crossover. We demonstrate the usefulness of the proposed methods through numerical studies mimicking the BNT162b2 phase 3 trial and the Prevent COVID U study. In addition, we assess how crossover and the frequency of diagnostic tests affect the precision of VE estimates.
| S-EPMC8406869 | biostudies-literature
Project description:Guided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (MPro). Of these tested small molecule medicines, six displayed an IC50 value in inhibiting MPro below 100 μM. Three medicines pimozide, ebastine, and bepridil are basic small molecules. Their uses in COVID-19 patients potentiate dual functions by both raising endosomal pH to slow SARS-CoV-2 entry into the human cell host and inhibiting MPro in infected cells. A live virus-based microneutralization assay showed that bepridil inhibited cytopathogenic effect induced by SARS-CoV-2 in Vero E6 cells completely at and dose-dependently below 5 μM and in A549 cells completely at and dose-dependently below 6.25 μM. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.
| S-EPMC7263498 | biostudies-literature
Project description:Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID-19), antivirals will remain an important adjunct to vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried out to identify agents that may provide clinical benefit to patients with COVID-19. Itraconazole, an antifungal agent, has been reported to have activity against animal coronaviruses. Using cell-based phenotypic assays, the in vitro antiviral activity of itraconazole and 17-OH itraconazole was assessed against clinical isolates from a German and Belgian patient infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Itraconazole demonstrated antiviral activity in human Caco-2 cells (EC50 = 2.3 µM; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay). Similarly, its primary metabolite, 17-OH itraconazole, showed inhibition of SARS-CoV-2 activity (EC50 = 3.6 µM). Remdesivir inhibited viral replication with an EC50 = 0.4 µM. Itraconazole and 17-OH itraconazole resulted in a viral yield reduction in vitro of approximately 2-log10 and approximately 1-log10 , as measured in both Caco-2 cells and VeroE6-eGFP cells, respectively. The viral yield reduction brought about by remdesivir or GS-441524 (parent nucleoside of the antiviral prodrug remdesivir; positive control) was more pronounced, with an approximately 3-log10 drop and >4-log10 drop in Caco-2 cells and VeroE6-eGFP cells, respectively. Itraconazole and 17-OH itraconazole exert in vitro low micromolar activity against SARS-CoV-2. Despite the in vitro antiviral activity, itraconazole did not result in a beneficial effect in hospitalized COVID-19 patients in a clinical study (EudraCT Number: 2020-001243-15).
| S-EPMC8014624 | biostudies-literature
Project description:Guided by a computational docking analysis, about 30 Food and Drug Administration/European Medicines Agency (FDA/EMA)-approved small-molecule medicines were characterized on their inhibition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). Of these small molecules tested, six displayed a concentration that inhibits response by 50% (IC50) value below 100 μM in inhibiting Mpro, and, importantly, three, that is, pimozide, ebastine, and bepridil, are basic molecules that potentiate dual functions by both raising endosomal pH to interfere with SARS-CoV-2 entry into the human cell host and inhibiting Mpro in infected cells. A live virus-based modified microneutralization assay revealed that bepridil possesses significant anti-SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration, 50% (EC50) values. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.
| S-EPMC7958448 | biostudies-literature
Project description:BackgroundThe sanitary emergency installed in the world, generated by the pandemic of COVID-19, instigates the search for scientific strategies to mitigate the damage caused by the disease to different sectors of society. The disease caused by the coronavirus, SARS-CoV-2, reached 216 countries/territories, where about 199 million people were reported with the infection. Of these, more than 4 million died. In this sense, strategies involving the development of new antiviral molecules are extremely important. The main protease (Mpro) from SARS-CoV-2 is an important target, which has been widely studied for antiviral treatment. This work aims to perform a screening of pharmacodynamics and pharmacokinetics of synthetic hybrids from thymoquinone and artemisin (THY-ART) against COVID-19.ResultsMolecular docking studies indicated that hybrids of artemisinin and thymoquinone showed a relevant interaction with the active fraction of the enzyme Mpro, when compared to the reference drugs. Furthermore, hybrids show an improvement in the interaction of substances with the enzyme, mainly due to the higher frequency of interactions with the Thr199 residue. ADMET studies indicated that hybrids tend to permeate biological membranes, allowing good human intestinal absorption, with low partition to the central nervous system, potentiation for CYP-450 enzyme inhibitors, low risk of toxicity compared to commercially available drugs, considering mainly mutagenicity and cardiotoxicity, low capacity of hybrids to permeate the blood-brain barrier, high absorption and moderate permeability in Caco-2 cells. In addition, T1-T7 tend to have a better distribution of their available fractions to carry out diffusion and transport across cell membranes, as well as increase the energy of interaction with the SARS-CoV-2 target.ConclusionsHybrid products of artemisinin and thymoquinone have the potential to inhibit Mpro, with desirable pharmacokinetic and toxicity characteristics compared to commercially available drugs, being indicated for preclinical and subsequent clinical studies against SARS-CoV-2. Emphasizing the possibility of synergistic use with currently used drugs in order to increase half-life and generate a possible synergistic effect. This work represents an important step for the development of specific drugs against COVID-19.
| S-EPMC8419828 | biostudies-literature
Project description:OBJECTIVES:At the end of November 2019, a novel coronavirus responsible for respiratory tract infections (COVID-19) emerged in China. Despite drastic containment measures, this virus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), spread in Asia and Europe. The pandemic is ongoing with particular hotspot in Southern Europe and America. Many studies predicted a similar epidemic in Africa as that currently seen in Europe and the United States of America. However, reported data do not confirm these predictions. One of the hypotheses that could explain the later emergence and spread of COVID-19 pandemic in African countries is the use of antimalarial drugs to treat malaria, and more particularly artemisinin-based combination therapy (ACT). METHODS:The antiviral activity of fixed concentrations of ACT at concentrations consistent with those observed in human plasma when ACT are administered at oral doses for uncomplicated malaria treatment was evaluated in vitro against clinically isolated SARS-CoV-2 strain (IHUMI-3) in Vero E6 cells. RESULTS:Mefloquine-artesunate exerted the highest antiviral activity with % inhibition of 72.1±18.3% at expected maximum blood concentration (Cmax) for each ACT drug at doses commonly administered in malaria treatment. All the other combinations, artesunate-amodiaquine, artemether-lumefantrine, artesunate-pyronaridine or dihydroartemisinin-piperaquine, showed antiviral inhibition in the same range (27.1 to 34.1%). CONCLUSIONS:Antimalarial drugs for which concentration data in lungs are available, are concentrated from 10 to 160 fold in lungs than in blood. These in vitro results reinforce the hypothesis that antimalarial drugs could be effective as anti-COVID-19 treatment.
| S-EPMC7426697 | biostudies-literature
Project description:The constant appearance of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VoCs) has jeopardized the protective capacity of approved vaccines against coronavirus disease-19 (COVID-19). For this reason, the generation of new vaccine candidates adapted to the emerging VoCs is of special importance. Here, we developed an optimized COVID-19 vaccine candidate using the modified vaccinia virus Ankara (MVA) vector to express a full-length prefusion-stabilized SARS-CoV-2 spike (S) protein, containing 3 proline (3P) substitutions in the S protein derived from the beta (B.1.351) variant, termed MVA-S(3Pbeta). Preclinical evaluation of MVA-S(3Pbeta) in head-to-head comparison to the previously generated MVA-S(3P) vaccine candidate, expressing a full-length prefusion-stabilized Wuhan S protein (with also 3P substitutions), demonstrated that two intramuscular doses of both vaccine candidates fully protected transgenic K18-hACE2 mice from a lethal challenge with SARS-CoV-2 beta variant, reducing mRNA and infectious viral loads in the lungs and in bronchoalveolar lavages, decreasing lung histopathological lesions and levels of proinflammatory cytokines in the lungs. Vaccination also elicited high titers of anti-S Th1-biased IgGs and neutralizing antibodies against ancestral SARS-CoV-2 Wuhan strain and VoCs alpha, beta, gamma, delta, and omicron. In addition, similar systemic and local SARS-CoV-2 S-specific CD4+ and CD8+ T-cell immune responses were elicited by both vaccine candidates after a single intranasal immunization in C57BL/6 mice. These preclinical data support clinical evaluation of MVA-S(3Pbeta) and MVA-S(3P), to explore whether they can diversify and potentially increase recognition and protection of SARS-CoV-2 VoCs.
| S-EPMC10754519 | biostudies-literature