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1.
Acta Biomed ; 93(2): e2022156, 2022 05 11.
Article in English | MEDLINE | ID: covidwho-1848005

ABSTRACT

Background and aim Recurrent wheezing is often triggered by viral respiratory infections. The aims of our study were: i) to evaluate whether the addition of a nutraceutical (Leucodif®), could improve the efficacy of montelukast or inhaled steroids (ICS) compared to the single treatment; ii) to verify whether a treatment is more effective than another. Our study was biased by the COVID-19 pandemic, which resulted in a lockdown of almost two months in Italy. Methods The multicenter, open-label study enrolled 84 children aged 2-6 years diagnosed with recurrent wheezing and randomized them into four treatment arms for three months: ICS treatment; ii) montelukast; iii) montelukast + Leucodif; iv) ICS + Leucodif. Children were assessed at baseline and after one, two, and three months of treatment using the TRACK score for both the caregiver and the physician. Results Out of the 84 patients, 18 patients received ICS therapy, 22 patients ICS + Leucodif, 24 patients montelukast, and 20 patients montelukast + Leucodif. All four treatments resulted in a significant reduction in symptoms with no differences among the various groups. Conclusions Our study demonstrates that montelukast therapy appears to be equally effective as ICS therapy and that the addition of the nutraceutical Leucodif does not appear to improve the treatment outcome. However, in our opinion our study was strongly influenced and biased by the lockdown due to the COVID-19 pandemic, which inherently resulted in reduced exposure to the viruses that commonly cause respiratory infections in children.


Subject(s)
Anti-Asthmatic Agents , Asthma , COVID-19 , Acetates , Administration, Inhalation , Anti-Asthmatic Agents/adverse effects , Asthma/drug therapy , Child , Communicable Disease Control , Cyclopropanes , Dietary Supplements , Humans , Pandemics , Quinolines , Respiratory Sounds , Steroids/therapeutic use , Sulfides
2.
Viruses ; 14(5)2022 04 21.
Article in English | MEDLINE | ID: covidwho-1822446

ABSTRACT

Coronaviruses (CoVs) consist of a large group of RNA viruses causing various diseases in humans and in lots of animals. Human coronavirus (HCoV) OC43, the prototype of beta-coronavirus discovered in the 1960s, has been circulating in humans for long time, and infection with other emerging strains of beta-coronavirus (SARS-CoV, SARS-CoV-2, and MERS-CoV) can lead to severe illness and death. In this study, we found that montelukast, a leukotriene receptor antagonist, potently inhibited the infection of HCoV-OC43 in distinct cells in a dose- and time- dependent manner. Additionally, the results showed that montelukast induced release of HCoV-OC43 genomic RNA by disrupting the integrity of the viral lipid membrane, and irreversibly inhibited viral infection. Considering the similarity among HCoV-OC43, MERS-CoV, and SARS-CoV-2, it suggests that montelukast may be a potential candidate for the treatment of human beta-coronavirus infection.


Subject(s)
COVID-19 , Coronavirus OC43, Human , Middle East Respiratory Syndrome Coronavirus , Acetates/pharmacology , Animals , COVID-19/drug therapy , Cyclopropanes , Quinolines , SARS-CoV-2 , Sulfides
3.
Nat Commun ; 13(1): 2268, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1815534

ABSTRACT

Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (Mpro) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the Mpro/BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor's keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the Mpro active site adapt to the inhibitor, which appears to be an intrinsic property of Mpro. Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with Mpro which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19 Vaccines , Coronavirus 3C Proteases , Cyclopropanes , Humans , Lactams , Leucine/analogs & derivatives , Nitriles , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Sulfones , Urea
4.
J Med Virol ; 94(5): 1950-1958, 2022 05.
Article in English | MEDLINE | ID: covidwho-1777576

ABSTRACT

The inflammatory/anti-inflammatory balance has an important role in the clinical course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease [COVID-19]) infection, which has affected over 200 million people since it first appeared in China in December 2019. This study aimed to determine the effectiveness of montelukast, which has known anti-inflammatory and bronchodilatory effects, in these patients. The prospective randomized controlled study included 180 patients who were hospitalized in the infectious diseases department of our hospital between May and July 2021 and were diagnosed with the delta variant of SARS-CoV-2 by real-time polymerase chain reaction of nasopharyngeal swabs. The patients were divided into three groups and received only standard treatment according to national guidelines (Group 1) or standard treatment plus 10 mg/day montelukast (Group 2) or 20 mg/day montelukast (Group 3). Laboratory parameters and pulmonary function tests (PFTs) at admission and on Day 5 of treatment were compared. Comparison of laboratory parameters on Day 5 showed that Groups 2 and 3 had significantly lower levels of lactate dehydrogenase, fibrinogen, D-dimer, C-reactive protein, and procalcitonin compared with Group 1 (p = 0.04, 0.002, 0.05, 0.03, and 0.04, respectively). In the comparison between Groups 2 and 3, only fibrinogen was significantly lower in Group 3 (p = 0.02). PFT results did not differ between the groups at admission, while on Day 5, only Group 3 showed significant improvements in forced expiratory volume in 1 s, forced vital capacity, and peak expiratory flow 25-75 compared with admission (p = 0.001 for all). Montelukast may be beneficial in COVID-19 patients to maintain the inflammatory/anti-inflammatory balance, prevent respiratory failure through its bronchodilator activity, and reduce mortality.


Subject(s)
COVID-19 , Acetates , COVID-19/drug therapy , Cyclopropanes , Humans , Prospective Studies , Quinolines , SARS-CoV-2 , Sulfides
5.
Br J Clin Pharmacol ; 88(8): 3562-3565, 2022 08.
Article in English | MEDLINE | ID: covidwho-1764882

ABSTRACT

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma) seem more susceptible to severe illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Under preclinical studies, roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline and right heart thickening. The current study reviewed existing data that the PDE-4 inhibitor, a roflumilast, protects renal tissues and other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related to a decrease in oxidative and inflammatory burden, caspase-3 suppression and increased protein kinase A (PKA)/cyclic A.M.P. (cAMP) levels in renal and other organ tissue.


Subject(s)
COVID-19 , Phosphodiesterase 4 Inhibitors , Aged , Aminopyridines/adverse effects , Benzamides , COVID-19/drug therapy , Cyclopropanes/adverse effects , Humans , Inflammation/drug therapy , Phosphodiesterase 4 Inhibitors/adverse effects , SARS-CoV-2
6.
Viruses ; 14(3)2022 03 16.
Article in English | MEDLINE | ID: covidwho-1742735

ABSTRACT

Enhancing treatment uptake for hepatitis C to achieve the elimination goals set by the World Health Organization could be achieved by reducing the treatment duration. The aim of this study was to compare the sustained virological response at week 12 (SVR12) after four weeks of glecaprevir/pibrentasvir (GLE/PIB) + ribavirin compared to eight weeks of GLE/PIB and to estimate predictors for SVR12 with four weeks of treatment through a multicenter open label randomized controlled trial. Patients were randomized 2:1 (4 weeks:8 weeks) and stratified by genotype 3 and were treatment naïve of all genotypes and without significant liver fibrosis. A total of 27 patients were analyzed for predictors for SVR12, including 15 from the first pilot phase of the study. In the 'modified intention to treat' group, 100% (7/7) achieved cure after eight weeks and for patients treated for four weeks the SVR12 was 58.3% (7/12). However, patients with a baseline viral load <2 mill IU/mL had 93% SVR12. The study closed prematurely due to the low number of included patients due to the COVID-19 pandemic. Our results suggest that viral load should be taken into account when considering trials of short course treatment.


Subject(s)
COVID-19 , Hepatitis C, Chronic , Aminoisobutyric Acids , Antiviral Agents/therapeutic use , Benzimidazoles , Cyclopropanes , Hepatitis C, Chronic/drug therapy , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Pandemics , Proline/analogs & derivatives , Pyrrolidines , Quinoxalines , Ribavirin/therapeutic use , Sulfonamides
7.
Trials ; 23(1): 19, 2022 Jan 06.
Article in English | MEDLINE | ID: covidwho-1677532

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic continues to affect the globe. After 18 months of the SARS-CoV-2 emergence, clinicians have clearly defined a subgroup of patients with lasting, disabling symptoms. While big strides have been made in understanding the acute phase of SARS-CoV-2 infection, the pathophysiology of long COVID is still largely unknown, and evidence-based, effective treatments for this condition remain unavailable. OBJECTIVES: To evaluate the efficacy of 10 mg oral montelukast every 24 h versus placebo in improving quality of life associated with mild to moderate respiratory symptoms in patients with long COVID as measured with the COPD Assessment Test (CAT) questionnaire. The secondary objectives will evaluate the effect of montelukast versus placebo on improving exercise capacity, COVID-19 symptoms (asthenia, headache, mental confusion or brain fog, ageusia, and anosmia), oxygen desaturation during exertion, functional status, and mortality. METHODS AND ANALYSIS: Phase III, randomized, double-blind clinical trial. We will include 18- to 80-year-old patients with SARS-CoV-2 infection and mild to moderate respiratory symptoms lasting more than 4 weeks. Participants will be randomly allocated in a 1:1 ratio to the intervention (experimental treatment with 10 mg/day montelukast) or the control group (placebo group), during a 28-day treatment. Follow-up will finish 56 days after the start of treatment. The primary outcome will be health-related quality of life associated with respiratory symptoms according to the COPD Assessment Test 4 weeks after starting the treatment. The following are the secondary outcomes: (a) exercise capacity and oxygen saturation (1-min sit-to-stand test); (b) Post-COVID-19 Functional Status Scale; (c) other symptoms: asthenia, headache, mental confusion (brain fog), ageusia, and anosmia (Likert scale); (d) use of healthcare resources; (e) mortality; (f) sick leave duration in days; and (g) side effects of montelukast. ETHICS AND DISSEMINATION: This study has been approved by the Clinical Research Ethics Committee of the IDIAPJGol (reference number 21/091-C). The trial results will be published in open access, peer-reviewed journals and explained in webinars to increase awareness and understanding about long COVID among primary health professionals. TRIAL REGISTRATION: ClinicalTrials.gov NCT04695704 . Registered on January 5, 2021. EudraCT number 2021-000605-24. Prospectively registered.


Subject(s)
COVID-19 , Acetates , COVID-19/complications , Cyclopropanes , Double-Blind Method , Humans , Quality of Life , Quinolines , Randomized Controlled Trials as Topic , SARS-CoV-2 , Sulfides , Treatment Outcome
8.
Int Immunopharmacol ; 103: 108412, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1568781

ABSTRACT

Levocetirizine, a third-generation antihistamine, and montelukast, a leukotriene receptor antagonist, exhibit remarkable synergistic anti-inflammatory activity across a spectrum of signaling proteins, cell adhesion molecules, and leukocytes. By targeting cellular protein activity, they are uniquely positioned to treat the symptoms of COVID-19. Clinical data to date with an associated six-month follow-up, suggests the combination therapy may prevent the progression of the disease from mild to moderate to severe, as well as prevent/treat many of the aspects of 'Long COVID,' thereby cost effectively reducing both morbidity and mortality. To investigate patient outcomes, 53 consecutive COVID-19 test (+) cases (ages 3-90) from a well-established, single-center practice in Boston, Massachusetts, between March - November 2020, were treated with levocetirizine and montelukast in addition to then existing protocols [2]. The data set was retrospectively reviewed. Thirty-four cases were considered mild (64%), 17 moderate (32%), and 2 (4%) severe. Several patients presented with significant comorbidities (obesity: n = 22, 41%; diabetes: n = 10, 19%; hypertension: n = 24, 45%). Among the cohort there were no exclusions, no intubations, and no deaths. The pilot study in Massachusetts encompassed the first COVID-19 wave which peaked on April 23, 2020 as well as the ascending portion of the second wave in the fall. During this period the average weekly COVID-19 case mortality rate (confirmed deaths/confirmed cases) varied considerably between 1 and 7.5% [37]. FDA has approved a multicenter, randomized, placebo-controlled, Phase 2 clinical trial design, replete with electronic diaries and laboratory metrics to explore scientific questions not addressed herein.


Subject(s)
Acetates/therapeutic use , COVID-19/drug therapy , Cetirizine/therapeutic use , Cyclopropanes/therapeutic use , Histamine H1 Antagonists, Non-Sedating/therapeutic use , Leukotriene Antagonists/therapeutic use , Quinolines/therapeutic use , SARS-CoV-2/drug effects , Sulfides/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Female , Humans , Male , Middle Aged , Retrospective Studies , Treatment Outcome , Young Adult
9.
Mol Ther ; 30(2): 963-974, 2022 02 02.
Article in English | MEDLINE | ID: covidwho-1525991

ABSTRACT

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).


Subject(s)
Acetates/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Cyclopropanes/pharmacology , Quinolines/pharmacology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Sulfides/pharmacology , A549 Cells , Acetates/chemistry , Angiotensin-Converting Enzyme 2/chemistry , Animals , Cell Survival/drug effects , Chlorocebus aethiops , Cyclopropanes/chemistry , Drug Repositioning , HEK293 Cells , Humans , Models, Molecular , Molecular Docking Simulation , Molecular Structure , Neutralization Tests , Protein Conformation , Quinolines/chemistry , SARS-CoV-2/drug effects , Serine Endopeptidases/chemistry , Sulfides/chemistry , Vero Cells , Virus Internalization/drug effects
10.
Nutrients ; 13(10)2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1463781

ABSTRACT

To date, vitamin D seems to have a significant role in affecting the prevention and immunomodulation in COVID-19 disease. Nevertheless, it is important to highlight that this pro-hormone has other several activities, such as affecting drug concentrations, since it regulates the expression of cytochrome P450 (CYP) genes. Efavirenz (EFV) pharmacokinetics is influenced by CYPs, but no data are available in the literature concerning the association among vitamin D levels, seasonality (which affects vitamin D concentrations) and EFV plasma levels. For this reason, the aim of this study was to evaluate the effect of 25-hydroxy vitamin D (25(OH)D3) levels on EFV plasma concentrations in different seasons. We quantified 25(OH)D3 by using chemiluminescence immunoassay, whereas EFV plasma concentrations were quantified with the HPLC-PDA method. A total of 316 patients were enrolled in Turin and Rome. Overall, 25(OH)D3levels resulted in being inversely correlated with EFV concentrations. Some patients with EFV levels higher than 4000 ng/mL showed a deficient 25(OH)D3 concentration in Turin and Rome cohorts and together. EFV concentrations were different in patients without vitamin D supplementation, whereas, for vitamin D-administered individuals, no difference in EFV exposure was present. Concerning seasonality, EFV concentrations were associated with 25(OH)D3 deficiency only in winter and in spring, whereas a significant influence was highlighted for 25(OH)D3 stratification for deficient, insufficient and sufficient values in winter, spring and summer. A strong and inverse association between 25(OH)D3and EFV plasma concentrations was suggested. These data suggest that vitamin D is able to affect drug exposure in different seasons; thus, the achievement of the clinical outcome could be improved by also considering this pro-hormone.


Subject(s)
Alkynes/blood , Alkynes/therapeutic use , Benzoxazines/blood , Benzoxazines/therapeutic use , Cyclopropanes/blood , Cyclopropanes/therapeutic use , HIV Infections/blood , HIV Infections/drug therapy , Vitamin D/pharmacology , Vitamins/pharmacology , Adult , Cohort Studies , Female , Humans , Italy , Male , Middle Aged , Retrospective Studies , Reverse Transcriptase Inhibitors/blood , Reverse Transcriptase Inhibitors/therapeutic use , Seasons , Treatment Outcome , Vitamin D/blood , Vitamins/blood
13.
Pharmacology ; 106(9-10): 469-476, 2021.
Article in English | MEDLINE | ID: covidwho-1344012

ABSTRACT

BACKGROUND: The coronavirus disease-19 (COVID-19) pandemic is a serious devastating disease and has posed a global health emergency. So far, there is not any specific therapy approved till date to control the clinical symptoms of the disease. Remdesivir has been approved by the FDA as an emergency clinical therapy. But it may not be effective alone to control the disease as it can only control the viral replication in the host. SUMMARY: This article summarizes the possible therapeutic potential and benefits of using montelukast, a cysteinyl leukotriene 1 (CysLT1) receptor antagonist, to control COVID-19 pathophysiology. Montelukast has shown anti-inflammatory effects, reduced cytokine production, improvement in post-infection cough production and other lung complications. Key Messages: Recent reports clearly indicate a distinct role of CysLT-regulated cytokines and immunological signaling in COVID-19. Thus, montelukast may have a clinical potential to control lung pathology during COVID-19.


Subject(s)
Acetates/pharmacology , COVID-19/drug therapy , Cyclopropanes/pharmacology , Leukotriene Antagonists/pharmacology , Quinolines/pharmacology , Sulfides/pharmacology , Acetates/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/metabolism , COVID-19/physiopathology , Cyclopropanes/therapeutic use , Humans , Leukotriene Antagonists/therapeutic use , Quinolines/therapeutic use , Receptors, Leukotriene/metabolism , Sulfides/therapeutic use
15.
Biochem Biophys Res Commun ; 571: 26-31, 2021 09 24.
Article in English | MEDLINE | ID: covidwho-1312941

ABSTRACT

The pandemic of SARS-CoV-2 has necessitated expedited research efforts towards finding potential antiviral targets and drug development measures. While new drug discovery is time consuming, drug repurposing has been a promising area for elaborate virtual screening and identification of existing FDA approved drugs that could possibly be used for targeting against functions of various proteins of SARS-CoV-2 virus. RNA dependent RNA polymerase (RdRp) is an important enzyme for the virus that mediates replication of the viral RNA. Inhibition of RdRp could inhibit viral RNA replication and thus new virus particle production. Here, we screened non-nucleoside antivirals and found three out of them to be strongest in binding to RdRp out of which two retained binding even using molecular dynamic simulations. We propose these two drugs as potential RdRp inhibitors which need further in-depth testing.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors , SARS-CoV-2/drug effects , SARS-CoV-2/enzymology , Amides/pharmacology , Antiviral Agents/chemistry , Benzimidazoles/pharmacology , COVID-19/virology , Carbamates/pharmacology , Catalytic Domain , Computer Simulation , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Cyclopropanes/pharmacology , Drug Evaluation, Preclinical , Drug Repositioning , Fluorenes/pharmacology , Humans , Lactams, Macrocyclic/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Proline/analogs & derivatives , Proline/pharmacology , Protein Conformation , Quinoxalines/pharmacology , Sulfonamides/pharmacology
16.
Eur J Pharmacol ; 904: 174196, 2021 Aug 05.
Article in English | MEDLINE | ID: covidwho-1230461

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the responsible agent for the coronavirus disease 2019 (Covid-19), has its entry point through interaction with angiotensin converting enzyme 2 (ACE2) receptors, highly expressed in lung type II alveolar cells and other tissues, like heart, pancreas, brain, and vascular endothelium. This review aimed to elucidate the potential role of leukotrienes (LTs) in the pathogenesis and clinical presentation of SARS-CoV-2 infection, and to reveal the critical role of LT pathway receptor antagonists and inhibitors in Covid-19 management. A literature search was done in PubMed, Scopus, Web of Science and Google Scholar databases to find the potential role of montelukast and other LT inhibitors in the management of pulmonary and extra-pulmonary manifestations triggered by SARS-CoV-2. Data obtained so far underline that pulmonary and extra-pulmonary manifestations in Covid-19 are attributed to a direct effect of SARS-CoV-2 in expressed ACE2 receptors or indirectly through NF-κB dependent induction of a cytokine storm. Montelukast can ameliorate extra-pulmonary manifestations in Covid-19 either directly through blocking of Cys-LTRs in different organs or indirectly through inhibition of the NF-κB signaling pathway.


Subject(s)
Acetates/therapeutic use , COVID-19/drug therapy , Cyclopropanes/therapeutic use , Leukotriene Antagonists/therapeutic use , Leukotrienes , Lung Diseases/drug therapy , Quinolines/therapeutic use , Signal Transduction/drug effects , Sulfides/therapeutic use , COVID-19/complications , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/etiology , Humans , Lung Diseases/etiology , Receptors, Leukotriene/drug effects
17.
Sci Rep ; 11(1): 10290, 2021 05 13.
Article in English | MEDLINE | ID: covidwho-1228274

ABSTRACT

As the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) pandemic engulfs millions worldwide, the quest for vaccines or drugs against the virus continues. The helicase protein of SARS-CoV-2 represents an attractive target for drug discovery since inhibition of helicase activity can suppress viral replication. Using in silico approaches, we have identified drugs that interact with SARS-CoV-2 helicase based on the presence of amino acid arrangements matching binding sites of drugs in previously annotated protein structures. The drugs exhibiting an RMSD of ≤ 3.0 Å were further analyzed using molecular docking, molecular dynamics (MD) simulation, and post-MD analyses. Using these approaches, we found 12 drugs that showed strong interactions with SARS-CoV-2 helicase amino acids. The analyses were performed using the recently available SARS-CoV-2 helicase structure (PDB ID: 5RL6). Based on the MM-GBSA approach, out of the 12 drugs, two drugs, namely posaconazole and grazoprevir, showed the most favorable binding energy, - 54.8 and - 49.1 kcal/mol, respectively. Furthermore, of the amino acids found conserved among all human coronaviruses, 10/11 and 10/12 were targeted by, respectively, grazoprevir and posaconazole. These residues are part of the crucial DEAD-like helicase C and DEXXQc_Upf1-like/ DEAD-like helicase domains. Strong interactions of posaconazole and grazoprevir with conserved amino acids indicate that the drugs can be potent against SARS-CoV-2. Since the amino acids are conserved among the human coronaviruses, the virus is unlikely to develop resistance mutations against these drugs. Since these drugs are already in use, they may be immediately repurposed for SARS-CoV-2 therapy.


Subject(s)
Amides/pharmacology , Carbamates/pharmacology , Cyclopropanes/pharmacology , Drug Repositioning , Enzyme Inhibitors/pharmacology , Quinoxalines/pharmacology , RNA Helicases/antagonists & inhibitors , SARS-CoV-2/enzymology , Sulfonamides/pharmacology , Triazoles/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Repositioning/methods , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Domains/drug effects , RNA Helicases/chemistry , RNA Helicases/metabolism , SARS-CoV-2/drug effects , Viral Proteins/antagonists & inhibitors , Viral Proteins/chemistry , Viral Proteins/metabolism
18.
Sci Rep ; 11(1): 7307, 2021 03 31.
Article in English | MEDLINE | ID: covidwho-1164913

ABSTRACT

Outcomes of various clinical studies for the coronavirus disease 2019 (COVID-19) treatment indicated that the drug acts via inhibition of multiple pathways (targets) is likely to be more successful and promising. Keeping this hypothesis intact, the present study describes for the first-time, Grazoprevir, an FDA approved anti-viral drug primarily approved for Hepatitis C Virus (HCV), mediated multiple pathway control via synergistic inhibition of viral entry targeting host cell Angiotensin-Converting Enzyme 2 (ACE-2)/transmembrane serine protease 2 (TMPRSS2) and viral replication targeting RNA-dependent RNA polymerase (RdRP). Molecular modeling followed by in-depth structural analysis clearly demonstrated that Grazoprevir interacts with the key residues of these targets. Futher, Molecular Dynamics (MD) simulations showed stability and burial of key residues after the complex formation. Finally, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) analysis identified the governing force of drug-receptor interactions and stability. Thus, we believe that Grazoprevir could be an effective therapeutics for the treatment of the COVID-19 pandemic with a promise of unlikely drug resistance owing to multiple inhibitions of eukaryotic and viral proteins, thus warrants further clinical studies.


Subject(s)
Amides/metabolism , Amides/pharmacology , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/pharmacology , Carbamates/metabolism , Carbamates/pharmacology , Coronavirus RNA-Dependent RNA Polymerase/metabolism , Cyclopropanes/metabolism , Cyclopropanes/pharmacology , Quinoxalines/metabolism , Quinoxalines/pharmacology , Sulfonamides/metabolism , Sulfonamides/pharmacology , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/metabolism , Coronavirus RNA-Dependent RNA Polymerase/chemistry , Drug Repositioning , Humans , Models, Molecular , Molecular Dynamics Simulation , Serine Endopeptidases/chemistry , Serine Endopeptidases/metabolism , Virus Internalization/drug effects
19.
J Comput Chem ; 42(13): 897-907, 2021 05 15.
Article in English | MEDLINE | ID: covidwho-1130516

ABSTRACT

SARS-CoV and SARS-CoV-2 belong to the subfamily Coronaviridae and infect humans, they are constituted by four structural proteins: Spike glycoprotein (S), membrane (M), envelope (E) and nucleocapsid (N), and nonstructural proteins, such as Nsp15 protein which is exclusively present on nidoviruses and is absent in other RNA viruses, making it an ideal target in the field of drug design. A virtual screening strategy to search for potential drugs was proposed, using molecular docking to explore a library of approved drugs available in the DrugBank database in order to identify possible NSP15 inhibitors to treat Covid19 disease. We found from the docking analysis that the antiviral drugs: Paritaprevir and Elbasvir, currently both approved for hepatitis C treatment which showed some of the lowest free binding energy values were considered as repositioning drugs to combat SARS-CoV-2. Furthermore, molecular dynamics simulations of the Apo and Holo-Nsp15 systems were performed in order to get insights about the stability of these protein-ligand complexes.


Subject(s)
Antiviral Agents/pharmacology , Benzofurans/pharmacology , COVID-19/drug therapy , Cyclopropanes/pharmacology , Endoribonucleases/antagonists & inhibitors , Imidazoles/pharmacology , Lactams, Macrocyclic/pharmacology , Proline/analogs & derivatives , SARS-CoV-2/drug effects , Sulfonamides/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , COVID-19/virology , Drug Repositioning , Endoribonucleases/metabolism , Humans , Molecular Docking Simulation , Molecular Targeted Therapy , Proline/pharmacology , SARS-CoV-2/metabolism , Viral Nonstructural Proteins/metabolism
20.
Biosci Rep ; 40(6)2020 06 26.
Article in English | MEDLINE | ID: covidwho-1099357

ABSTRACT

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Subject(s)
Betacoronavirus/enzymology , Maraviroc/pharmacology , Protease Inhibitors/pharmacology , Quinoxalines/pharmacology , Sulfonamides/pharmacology , Aminoisobutyric Acids , Antiviral Agents/chemistry , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Computer Simulation , Cyclopropanes , Drug Evaluation, Preclinical/methods , Lactams, Macrocyclic , Leucine/analogs & derivatives , Maraviroc/chemistry , Maraviroc/metabolism , Molecular Structure , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Protease Inhibitors/metabolism , Quinoxalines/chemistry , Quinoxalines/metabolism , SARS-CoV-2 , Sulfonamides/chemistry , Sulfonamides/metabolism
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