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1.
Eur Rev Med Pharmacol Sci ; 25(1 Suppl): 90-100, 2021 12.
Article in English | MEDLINE | ID: covidwho-1566967

ABSTRACT

OBJECTIVE: The aim of the study was to show the effect that two naturally occurring compounds, a cyclodextrin and hydroxytyrosol, can have on the entry of SARS-CoV-2 into human cells. MATERIALS AND METHODS: The PubMed database was searched to retrieve studies published from 2000 to 2020, satisfying the inclusion criteria. The search keywords were: SARS-CoV, SARS-CoV-2, coronavirus, lipid raft, endocytosis, hydroxytyrosol, cyclodextrin. Modeling of alpha-cyclodextrin and hydroxytyrosol were done using UCSF Chimera 1.14. RESULTS: The search results indicated that cyclodextrins can reduce the efficiency of viral endocytosis and that hydroxytyrosol has antiviral properties. Bioinformatic docking studies showed that alpha-cyclodextrin and hydroxytyrosol, alone or in combination, interact with the viral spike protein and its host cell receptor ACE2, thereby potentially influencing the endocytosis process. CONCLUSIONS: Hydroxytyrosol and alpha-cyclodextrin can be useful against the spread of SARS-CoV-2.


Subject(s)
Phenylethyl Alcohol/analogs & derivatives , SARS-CoV-2/physiology , Virus Internalization/drug effects , alpha-Cyclodextrins/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Binding Sites , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Computational Biology/methods , Humans , Membrane Microdomains/drug effects , Membrane Microdomains/metabolism , Membrane Microdomains/virology , Molecular Docking Simulation , Phenylethyl Alcohol/chemistry , Phenylethyl Alcohol/metabolism , Phenylethyl Alcohol/pharmacology , Phenylethyl Alcohol/therapeutic use , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , alpha-Cyclodextrins/chemistry , alpha-Cyclodextrins/metabolism , alpha-Cyclodextrins/therapeutic use
2.
Eur Rev Med Pharmacol Sci ; 25(1 Suppl): 81-89, 2021 12.
Article in English | MEDLINE | ID: covidwho-1566966

ABSTRACT

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of α-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans. PATIENTS AND METHODS: For in vitro experiments on Vero E6 cells, RNA for RT-qPCR analysis was extracted from Caco2 and human fibroblast cell lines. For study in humans, the treatment group consisted of 149 healthy volunteers in Northern Cyprus, considered at higher risk of SARS-CoV-2 infection than the general population. The volunteers used nasal spray containing α-cyclodextrin and hydroxytyrosol for 4 weeks. The control group consisted of 76 healthy volunteers who did not use the spray. RESULTS: RT-qPCR experiments on targeted genes involved in endocytosis showed a reduction in gene expression, whereas cytotoxicity and cytoprotective tests showed that the compounds exerted a protective effect against SARS-CoV-2 infection at non-cytotoxic concentrations. None of the volunteers became positive to SARS-CoV-2 RT-qPCR assay during the 30 days of treatment. CONCLUSIONS: Treatment with α-cyclodextrin and hydroxytyrosol nasal spray improved defenses against SARS-CoV-2 infection and reduced synthesis of viral particles.


Subject(s)
Anti-Infective Agents/pharmacology , Phenylethyl Alcohol/analogs & derivatives , SARS-CoV-2/drug effects , Virus Internalization/drug effects , alpha-Cyclodextrins/pharmacology , Administration, Intranasal , Adult , Aged , Animals , Anti-Infective Agents/administration & dosage , COVID-19/pathology , COVID-19/prevention & control , COVID-19/virology , Cell Line , Chlorocebus aethiops , Female , Gene Expression/drug effects , Health Personnel/statistics & numerical data , Humans , Male , Middle Aged , Phenylethyl Alcohol/administration & dosage , Phenylethyl Alcohol/pharmacology , RNA, Viral/analysis , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Young Adult , alpha-Cyclodextrins/administration & dosage
3.
Eur Rev Med Pharmacol Sci ; 25(1 Suppl): 67-73, 2021 12.
Article in English | MEDLINE | ID: covidwho-1566965

ABSTRACT

A vast majority of COVID-19 patients experience fatigue, extreme tiredness and symptoms that persist beyond the active phase of the disease. This condition is called post-COVID syndrome. The mechanisms by which the virus causes prolonged illness are still unclear. The aim of this review is to gather information regarding post-COVID syndrome so as to highlight its etiological basis and the nutritional regimes and supplements that can mitigate, alleviate or relieve the associated chronic fatigue, gastrointestinal disorders and continuing inflammatory reactions. Naturally-occurring food supplements, such as acetyl L-carnitine, hydroxytyrosol and vitamins B, C and D hold significant promise in the management of post-COVID syndrome. In this pilot observational study, we evaluated the effect of a food supplement containing hydroxytyrosol, acetyl L-carnitine and vitamins B, C and D in improving perceived fatigue in patients who recovered from COVID-19 but had post-COVID syndrome characterized by chronic fatigue. The results suggest that the food supplement could proceed to clinical trials of its efficacy in aiding the recovery of patients with long COVID.


Subject(s)
COVID-19/complications , Dietary Supplements , Acetylcarnitine/administration & dosage , Adult , Aged , COVID-19/diet therapy , COVID-19/pathology , COVID-19/psychology , COVID-19/virology , Dietary Supplements/adverse effects , Fatigue/etiology , Female , Gastrointestinal Diseases/etiology , Humans , Male , Middle Aged , Phenylethyl Alcohol/administration & dosage , Phenylethyl Alcohol/analogs & derivatives , Pilot Projects , SARS-CoV-2/isolation & purification , Self Report , Surveys and Questionnaires , Vitamins/administration & dosage
4.
Arch Microbiol ; 203(6): 3557-3564, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1216209

ABSTRACT

The angiotensin-converting enzyme (ACE)-related carboxypeptidase, ACE-II, is a type I integral membrane protein of 805 amino acids that contains 1 HEXXH-E zinc binding consensus sequence. ACE-II has been implicated in the regulation of heart function and also as a functional receptor for the coronavirus that causes the severe acute respiratory syndrome (SARS). In this study, the potential of some flavonoids presents in propolis to bind to ACE-II receptors was calculated with in silico. Binding constants of ten flavonoids, caffeic acid, caffeic acid phenethyl ester, chrysin, galangin, myricetin, rutin, hesperetin, pinocembrin, luteolin and quercetin were measured using the AutoDock 4.2 molecular docking program. And also, these binding constants were compared to reference ligand of MLN-4760. The results are shown that rutin has the best inhibition potentials among the studied molecules with high binding energy - 8.04 kcal/mol, and it is followed by myricetin, quercetin, caffeic acid phenethyl ester and hesperetin. However, the reference molecule has binding energy of - 7.24 kcal/mol. In conclusion, the high potential of flavonoids in ethanolic propolis extracts to bind to ACE-II receptors indicates that this natural bee product has high potential for COVID-19 treatment, but this needs to be supported by experimental studies.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , COVID-19/drug therapy , Propolis/pharmacology , Animals , Bees , Caffeic Acids , Flavanones , Flavonoids , Hesperidin , Humans , Luteolin , Molecular Docking Simulation , Phenylethyl Alcohol/analogs & derivatives , Plant Extracts , Quercetin , Rutin
5.
Viruses ; 13(2)2021 02 02.
Article in English | MEDLINE | ID: covidwho-1154509

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally. Although measures to control SARS-CoV-2, namely, vaccination, medication, and chemical disinfectants are being investigated, there is an increase in the demand for auxiliary antiviral approaches using natural compounds. Here we have focused on hydroxytyrosol (HT)-rich aqueous olive pulp extract (HIDROX®) and evaluated its SARS-CoV-2-inactivating activity in vitro. We showed that the HIDROX solution exhibits time- and concentration-dependent SARS-CoV-2-inactivating activities, and that HIDROX has more potent virucidal activity than pure HT. The evaluation of the mechanism of action suggested that both HIDROX and HT induced structural changes in SARS-CoV-2, which changed the molecular weight of the spike proteins. Even though the spike protein is highly glycosylated, this change was induced regardless of the glycosylation status. In addition, HIDROX or HT treatment disrupted the viral genome. Moreover, the HIDROX-containing cream applied on film showed time- and concentration-dependent SARS-CoV-2-inactivating activities. Thus, the HIDROX-containing cream can be applied topically as an antiviral hand cream. Our findings suggest that HIDROX contributes to improving SARS-CoV-2 control measures.


Subject(s)
Antiviral Agents/pharmacology , Olea , Phenylethyl Alcohol/analogs & derivatives , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Administration, Topical , Animals , Antiviral Agents/chemistry , Carbohydrates/chemistry , Chlorocebus aethiops , Coronavirus Nucleocapsid Proteins/chemistry , Genome, Viral/drug effects , Glycosylation , Microbial Sensitivity Tests , Phenylethyl Alcohol/administration & dosage , Phenylethyl Alcohol/pharmacology , Phosphoproteins/chemistry , Plant Extracts/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Skin Cream , Spike Glycoprotein, Coronavirus/chemistry , Vero Cells , Virus Inactivation/drug effects
6.
Acta Biomed ; 91(13-S): e2020022, 2020 11 09.
Article in English | MEDLINE | ID: covidwho-918593

ABSTRACT

BACKGROUND AND AIM OF THE WORK: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemics. This virus attacks the cells by binding to the transmembrane angiotensin I converting enzyme 2. In this study, we experimented a food supplement containing alpha-cyclodextrin and hydroxytyrosol for the improvement of the defenses against the SARS-CoV-2. Hydroxytyrosol has anti-viral properties and is able to reduce the serum lipids in mice. α-cyclodextrin has the ability to deplete sphingolipids and phospholipids from the cellular membranes. The aim of the present preliminary open non-controlled interventional study was to evaluate the efficacy of alpha-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2. METHODS: Fifty healthy volunteers at a higher risk of SARS-CoV-2 infection from Northern Cyprus and six positive individuals for SARS-CoV-2 were enrolled in this study. The in silico prediction was performed using D3DOCKING to evaluate the interactions of hydroxytyrosol and alpha-cyclodextrin with proteins involved in the SARS-CoV-2 endocytosis. RESULTS: The 50 volunteers did not become positive in 15 days for SARS-CoV-2 after the administration of the compound for two weeks, despite they were at higher risk of infection than the general population. Interestingly, in the cohort of six positive patients, two patients were administered the spray and became negative after five days, despite the viral load was higher in the treated subjects than the untreated patients who became negative after ten days. In addition, we identified possible interactions among hydroxytyrosol and alpha-cyclodextrin with the protein Spike and the human proteins ACE2 and TMPRSS2. CONCLUSIONS: We reported on the results of the possible role of alpha-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2. The next step will be the administration of the compound to a larger cohort in a controlled study to confirm the reduction of the infection rate of SARS-CoV-2 in the treated subjects.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/prevention & control , Coronavirus Infections/transmission , Pandemics/prevention & control , Phenylethyl Alcohol/analogs & derivatives , Pneumonia, Viral/prevention & control , Pneumonia, Viral/transmission , alpha-Cyclodextrins/therapeutic use , Adult , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/drug therapy , Cyprus , Endocytosis/drug effects , Female , Humans , Male , Middle Aged , Oral Sprays , Phenylethyl Alcohol/therapeutic use , Pilot Projects , Pneumonia, Viral/diagnosis , SARS-CoV-2 , Viral Load
7.
Acta Biomed ; 91(13-S): e2020009, 2020 11 09.
Article in English | MEDLINE | ID: covidwho-918592

ABSTRACT

BACKGROUND AND AIM OF THE WORK: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current pandemics of coronavirus disease. This virus is able to attack the cells of the airway epithelium by binding to the transmembrane angiotensin I converting enzyme 2 (ACE2). We developed an oral spray that could inhibit the SARS-CoV-2 endocytosis. The spray contains hydroxytyrosol for its anti-viral, anti-inflammatory and anti-oxidant properties, and α-cyclodextrin for its ability to deplete sphingolipids, that form the lipid rafts where ACE2 localizes. The aim of the present pilot multi-centric open non-controlled observational study was to evaluate the safety profile of the "Endovir Stop" spray. METHODS: An MTT test was performed to evaluate cytotoxicity of the spray in two human cell lines. An oxygen radical absorbance capacity assay was performed to evaluate the antioxidant capacity of the spray. The spray was also tested on 87 healthy subjects on a voluntary basis. RESULTS: The MTT test revealed that the spray is not cytotoxic. The ORAC assay showed a good antioxidant capacity for the spray. Endovir Stop tested on healthy volunteers showed the total absence of side effects and drug interactions during the treatment. CONCLUSIONS: We demonstrated that Endovir Stop spray is safe. The next step would be the administration of the efficacy of the spray by testing it to a wider range of people and see whether there is a reduced infection rate of SARS-CoV-2 in the treated subjects than in the non-treated individuals.


Subject(s)
Antiviral Agents/adverse effects , Betacoronavirus , Coronavirus Infections/drug therapy , Endocytosis/drug effects , Phenylethyl Alcohol/analogs & derivatives , Pneumonia, Viral/drug therapy , alpha-Cyclodextrins/adverse effects , Adult , Aged , Aged, 80 and over , COVID-19 , Caco-2 Cells , Cell Culture Techniques , Female , Humans , Male , Middle Aged , Oral Sprays , Pandemics , Phenylethyl Alcohol/adverse effects , Pilot Projects , SARS-CoV-2 , Young Adult
8.
J Biomol Struct Dyn ; 39(11): 3842-3854, 2021 07.
Article in English | MEDLINE | ID: covidwho-324383

ABSTRACT

The recent novel coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2/2019-nCoV) has caused a large number of deaths around the globe. There is an urgent need to understand this new virus and develop prophylactic and therapeutic drugs. Since drug development is an expensive, intense and time-consuming path, timely repurposing of the existing drugs is often explored wherein the research avenues including genomics, bioinformatics, molecular modeling approaches offer valuable strengths. Here, we have examined the binding potential of Withaferin-A (Wi-A), Withanone (Wi-N) (active withanolides of Ashwagandha) and Caffeic Acid Phenethyl Ester (CAPE, bioactive ingredient of propolis) to a highly conserved protein, Mpro of SARS-CoV-2. We found that Wi-N and CAPE, but not Wi-A, bind to the substrate-binding pocket of SARS-CoV-2 Mpro with efficacy and binding energies equivalent to an already claimed N3 protease inhibitor. Similar to N3 inhibitor, Wi-N and CAPE were interacting with the highly conserved residues of the proteases of coronaviruses. The binding stability of these molecules was further analyzed using molecular dynamics simulations. The binding free energies calculated using MM/GBSA for N3 inhibitor, CAPE and Wi-N were also comparable. Data presented here predicted that these natural compounds may possess the potential to inhibit the functional activity of SARS-CoV-2 protease (an essential protein for virus survival), and hence (i) may connect to save time and cost required for designing/development, and initial screening for anti-COVID drugs, (ii) may offer some therapeutic value for the management of novel fatal coronavirus disease, (iii) warrants prioritized further validation in the laboratory and clinical tests.Communicated by Ramaswamy H. Sarma.


Subject(s)
COVID-19 , SARS-CoV-2 , Caffeic Acids , Humans , Molecular Docking Simulation , Peptide Hydrolases , Phenylethyl Alcohol/analogs & derivatives , Protease Inhibitors/pharmacology , Withanolides
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