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1.
Molecules ; 27(10)2022 May 18.
Article in English | MEDLINE | ID: covidwho-1875715

ABSTRACT

Data from the World Health Organisation show that the global incidence of dengue infection has risen drastically, with an estimated 400 million cases of dengue infection occurring annually. Despite this worrying trend, there is still no therapeutic treatment available. Herein, we investigated short peptide fragments with a varying total number of amino acid residues (peptide fragments) from previously reported dengue virus type 2 (DENV2) peptide-based inhibitors, DN58wt (GDSYIIIGVEPGQLKENWFKKGSSIGQMF), DN58opt (TWWCFYFCRRHHPFWFFYRHN), DS36wt (LITVNPIVTEKDSPVNIEAE), and DS36opt (RHWEQFYFRRRERKFWLFFW), aided by in silico approaches: peptide-protein molecular docking and 100 ns of molecular dynamics (MD) simulation via molecular mechanics using Poisson-Boltzmann surface area (MMPBSA) and molecular mechanics generalised Born surface area (MMGBSA) methods. A library of 11,699 peptide fragments was generated, subjected to in silico calculation, and the candidates with the excellent binding affinity and shown to be stable in the DI-DIII binding pocket of DENV2 envelope (E) protein were determined. Selected peptides were synthesised using conventional Fmoc solid-phase peptide chemistry, purified by RP-HPLC, and characterised using LCMS. In vitro studies followed, to test for the peptides' toxicity and efficacy in inhibiting the DENV2 growth cycle. Our studies identified the electrostatic interaction (from free energy calculation) to be the driving stabilising force for the E protein-peptide interactions. Five key E protein residues were also identified that had the most interactions with the peptides: (polar) LYS36, ASN37, and ARG350, and (nonpolar) LEU351 and VAL354; these residues might play crucial roles in the effective binding interactions. One of the peptide fragments, DN58opt_8-13 (PFWFFYRH), showed the best inhibitory activity, at about 63% DENV2 plague reduction, compared with no treatment. This correlates well with the in silico studies in which the peptide possessed the lowest binding energy (-9.0 kcal/mol) and was maintained steadily within the binding pocket of DENV2 E protein during the MD simulations. This study demonstrates the use of computational studies to expand research on lead optimisation of antiviral peptides, thus explaining the inhibitory potential of the designed peptides.


Subject(s)
Dengue Virus , Dengue , Dengue/drug therapy , Humans , Molecular Docking Simulation , Peptide Fragments/pharmacology , Peptides/chemistry
2.
Chem Commun (Camb) ; 58(11): 1804-1807, 2022 Feb 03.
Article in English | MEDLINE | ID: covidwho-1639537

ABSTRACT

We present the finding of a dimeric ACE2 peptide mimetic designed through side chain cross-linking and covalent dimerization. It has a binding affinity of 16 nM for the SARS-CoV-2 spike RBD, and effectively inhibits the SARS-CoV-2 pseudovirus in Huh7-hACE2 cells with an IC50 of 190 nM and neutralizes the authentic SARS-CoV-2 in Caco2 cells with an IC50 of 2.4 µM. Our study should provide a new insight for the optimization of peptide-based anti-SARS-CoV-2 inhibitors.


Subject(s)
Antiviral Agents/pharmacology , Peptide Fragments/pharmacology , Peptidomimetics/pharmacology , SARS-CoV-2/drug effects , Amino Acid Sequence , Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Cell Line, Tumor , Humans , Microbial Sensitivity Tests , Peptide Fragments/chemical synthesis , Peptide Fragments/metabolism , Peptidomimetics/chemical synthesis , Peptidomimetics/metabolism , Protein Binding , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
3.
Biosci Rep ; 41(12)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1592575

ABSTRACT

Parasporin-2Aa1 (PS2Aa1) is a toxic protein of 37 KDa (30 kDa, activated form produced by proteolysis) that was shown to be cytotoxic against specific human cancer cells, although its mechanism of action has not been elucidated yet. In order to study the role of some native peptide fragments of proteins on anticancer activity, here we investigated the cytotoxic effect of peptide fragments from domain-1 of PS2Aa1 and one of the loops present in the binding region of the virus spike protein from Alphacoronavirus (HCoV-229E), the latter according to scientific reports, who showed interaction with the human APN (h-APN) receptor, evidence corroborated through computational simulations, and thus being possible active against colon cancer cells. Peptides namely P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa were synthesized using the Fmoc solid-phase synthesis and characterized by mass spectrometry (MS). Additionally, one region from loop 1 of HCoV-229E, Loop1-HCoV-229E, was also synthesized and characterized. The A4W-GGN5 anticancer peptide and 5-fluorouracil (5-FU) were taken as a control in all experiments. Circular dichroism revealed an α-helix structure for the peptides derived from PS2Aa1 (P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa) and ß-laminar structure for the peptide derived from Alphacoronavirus spike protein Loop1-HCoV-229E. Peptides showed a hemolysis percentage of less than 20% at 100 µM concentration. Besides, peptides exhibited stronger anticancer activity against SW480 and SW620 cells after exposure for 48 h. Likewise, these compounds showed significantly lower toxicity against normal cells CHO-K1. The results suggest that native peptide fragments from Ps2Aa1 may be optimized as a novel potential cancer-therapeutic agents.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Endotoxins/pharmacology , Peptide Fragments/pharmacology , Spike Glycoprotein, Coronavirus/pharmacology , Alphacoronavirus , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , CD13 Antigens/metabolism , CHO Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cricetulus , Endotoxins/toxicity , Hemolysis/drug effects , Humans , Molecular Docking Simulation , Peptide Fragments/chemical synthesis , Peptide Fragments/toxicity , Protein Conformation, alpha-Helical , Sheep, Domestic , Spike Glycoprotein, Coronavirus/toxicity , Structure-Activity Relationship
4.
Biosci Rep ; 41(12)2021 12 22.
Article in English | MEDLINE | ID: covidwho-1526113

ABSTRACT

Parasporin-2Aa1 (PS2Aa1) is a toxic protein of 37 KDa (30 kDa, activated form produced by proteolysis) that was shown to be cytotoxic against specific human cancer cells, although its mechanism of action has not been elucidated yet. In order to study the role of some native peptide fragments of proteins on anticancer activity, here we investigated the cytotoxic effect of peptide fragments from domain-1 of PS2Aa1 and one of the loops present in the binding region of the virus spike protein from Alphacoronavirus (HCoV-229E), the latter according to scientific reports, who showed interaction with the human APN (h-APN) receptor, evidence corroborated through computational simulations, and thus being possible active against colon cancer cells. Peptides namely P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa were synthesized using the Fmoc solid-phase synthesis and characterized by mass spectrometry (MS). Additionally, one region from loop 1 of HCoV-229E, Loop1-HCoV-229E, was also synthesized and characterized. The A4W-GGN5 anticancer peptide and 5-fluorouracil (5-FU) were taken as a control in all experiments. Circular dichroism revealed an α-helix structure for the peptides derived from PS2Aa1 (P264-G274, Loop1-PS2Aa, and Loop2-PS2Aa) and ß-laminar structure for the peptide derived from Alphacoronavirus spike protein Loop1-HCoV-229E. Peptides showed a hemolysis percentage of less than 20% at 100 µM concentration. Besides, peptides exhibited stronger anticancer activity against SW480 and SW620 cells after exposure for 48 h. Likewise, these compounds showed significantly lower toxicity against normal cells CHO-K1. The results suggest that native peptide fragments from Ps2Aa1 may be optimized as a novel potential cancer-therapeutic agents.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Endotoxins/pharmacology , Peptide Fragments/pharmacology , Spike Glycoprotein, Coronavirus/pharmacology , Alphacoronavirus , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/toxicity , CD13 Antigens/metabolism , CHO Cells , Cell Line, Tumor , Cell Proliferation/drug effects , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Cricetulus , Endotoxins/toxicity , Hemolysis/drug effects , Humans , Molecular Docking Simulation , Peptide Fragments/chemical synthesis , Peptide Fragments/toxicity , Protein Conformation, alpha-Helical , Sheep, Domestic , Spike Glycoprotein, Coronavirus/toxicity , Structure-Activity Relationship
5.
Biochim Biophys Acta Biomembr ; 1864(2): 183821, 2022 02 01.
Article in English | MEDLINE | ID: covidwho-1519618

ABSTRACT

Membrane-enveloped viruses are a major cause of global health challenges, including recent epidemics and pandemics. This mini-review covers the latest efforts to develop membrane-targeting antiviral peptides that inhibit enveloped viruses by 1) preventing virus-cell fusion or 2) disrupting the viral membrane envelope. The corresponding mechanisms of antiviral activity are discussed along with peptide engineering strategies to modulate membrane-peptide interactions in terms of potency and selectivity. Application examples are presented demonstrating how membrane-targeting antiviral peptides are useful therapeutics and prophylactics in animal models, while a stronger emphasis on biophysical concepts is proposed to refine mechanistic understanding and support potential clinical translation.


Subject(s)
Antiviral Agents/pharmacology , Cell Membrane/drug effects , Peptide Fragments/pharmacology , Virus Internalization , Viruses/drug effects , Animals , Humans
7.
Viruses ; 13(8)2021 08 23.
Article in English | MEDLINE | ID: covidwho-1367926

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in a global pandemic causing over 195 million infections and more than 4 million fatalities as of July 2021.To date, it has been demonstrated that a number of mutations in the spike glycoprotein (S protein) of SARS-CoV-2 variants of concern abrogate or reduce the neutralization potency of several therapeutic antibodies and vaccine-elicited antibodies. Therefore, the development of additional vaccine platforms with improved supply and logistic profile remains a pressing need. In this work, we have validated the applicability of a peptide-based strategy focused on a preventive as well as a therapeutic purpose. On the basis of the involvement of the dipeptidyl peptidase 4 (DPP4), in addition to the angiotensin converting enzyme 2 (ACE2) receptor in the mechanism of virus entry, we analyzed peptides bearing DPP4 sequences by protein-protein docking and assessed their ability to block pseudovirus infection in vitro. In parallel, we have selected and synthetized peptide sequences located within the highly conserved receptor-binding domain (RBD) of the S protein, and we found that RBD-based vaccines could better promote elicitation of high titers of neutralizing antibodies specific against the regions of interest, as confirmed by immunoinformatic methodologies and in vivo studies. These findings unveil a key antigenic site targeted by broadly neutralizing antibodies and pave the way to the design of pan-coronavirus vaccines.


Subject(s)
Dipeptidyl Peptidase 4/chemistry , Peptide Fragments/immunology , Peptide Fragments/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Broadly Neutralizing Antibodies/immunology , COVID-19/drug therapy , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Dipeptidyl Peptidase 4/metabolism , Epitopes, T-Lymphocyte/immunology , Humans , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Fragments/chemistry , Peptide Fragments/metabolism , Protein Binding , Protein Domains , Receptors, Coronavirus/chemistry , Receptors, Coronavirus/metabolism , SARS-CoV-2/chemistry , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells , Virus Internalization
8.
Emerg Microbes Infect ; 10(1): 810-821, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1180458

ABSTRACT

EK1 peptide is a membrane fusion inhibitor with broad-spectrum activity against human coronaviruses (CoVs). In the outbreak of COVID-19, we generated a lipopeptide EK1V1 by modifying EK1 with cholesterol, which exhibited significantly improved antiviral activity. In this study, we surprisingly found that EK1V1 also displayed potent cross-inhibitory activities against divergent HIV-1, HIV-2, and simian immunodeficiency virus (SIV) isolates. Consistently, the recently reported EK1 derivative EK1C4 and SARS-CoV-2 derived fusion inhibitor lipopeptides (IPB02 ∼ IPB09) also inhibited HIV-1 Env-mediated cell-cell fusion and infection efficiently. In the inhibition of a panel of HIV-1 mutants resistant to HIV-1 fusion inhibitors, EK1V1 and IPB02-based inhibitors exhibited significantly decreased or increased activities, suggesting the heptad repeat-1 region (HR1) of HIV-1 gp41 being their target. Furthermore, the sequence alignment and molecular docking analyses verified the target site and revealed the mechanism underlying the resistance. Combined, we conclude that this serendipitous discovery provides a proof-of-concept for a common mechanism of viral fusion and critical information for the development of broad-spectrum antivirals.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus/drug effects , HIV-1/drug effects , HIV-2/drug effects , Simian Immunodeficiency Virus/drug effects , Virus Internalization/drug effects , Amino Acid Sequence , Animals , Antiviral Agents/isolation & purification , Dose-Response Relationship, Drug , HIV Fusion Inhibitors/isolation & purification , HIV Fusion Inhibitors/pharmacology , Humans , Lipopeptides/isolation & purification , Lipopeptides/pharmacology , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Fragments/isolation & purification , Peptide Fragments/pharmacology , SARS-CoV-2/drug effects , Structure-Activity Relationship , Virus Replication/drug effects
9.
Eur Respir J ; 57(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1041881

ABSTRACT

Epidemiological data from the SARS-CoV-2 outbreak suggest sex differences in mortality and vulnerability; however, sex-dependent incidence of acute respiratory distress syndrome (ARDS) remains controversial and the sex-dependent mechanisms of endothelial barrier regulation are unknown. In premenopausal women, increased signalling of angiotensin (Ang)(1-7) via the Mas receptor has been linked to lower cardiovascular risk. Since stimulation of the Ang(1-7)/Mas axis protects the endothelial barrier in acute lung injury (ALI), we hypothesised that increased Ang(1-7)/Mas signalling may protect females over males in ALI/ARDS.Clinical data were collected from Charité inpatients (Berlin) and sex differences in ALI were assessed in wild-type (WT) and Mas-receptor deficient (Mas-/- ) mice. Endothelial permeability was assessed as weight change in isolated lungs and as transendothelial electrical resistance (TEER) in vitroIn 734 090 Charité inpatients (2005-2016), ARDS had a higher incidence in men as compared to women. In murine ALI, male WT mice had more lung oedema, protein leaks and histological evidence of injury than female WT mice. Lung weight change in response to platelet-activating factor (PAF) was more pronounced in male WT and female Mas-/- mice than in female WT mice, whereas Mas-receptor expression was higher in female WT lungs. Ovariectomy attenuated protection in female WT mice and reduced Mas-receptor expression. Oestrogen increased Mas-receptor expression and attenuated endothelial leakage in response to thrombin in vitro This effect was alleviated by Mas-receptor blockade.Improved lung endothelial barrier function protects female mice from ALI-induced lung oedema. This effect is partially mediated via enhanced Ang(1-7)/Mas signalling as a result of oestrogen-dependent Mas expression.


Subject(s)
Acute Lung Injury/genetics , Angiotensin I/metabolism , COVID-19/epidemiology , Capillary Permeability/genetics , Endothelium, Vascular/metabolism , Estrogens/metabolism , Lung/metabolism , Peptide Fragments/metabolism , Proto-Oncogene Proteins/genetics , Receptors, G-Protein-Coupled/genetics , Respiratory Distress Syndrome/epidemiology , Acute Lung Injury/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Angiotensin I/pharmacology , Angiotensin-Converting Enzyme 2 , Animals , Capillary Permeability/drug effects , Child , Electric Impedance , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Estradiol/pharmacology , Female , Humans , In Vitro Techniques , Lung/drug effects , Male , Mice , Mice, Knockout , Middle Aged , Ovariectomy , Peptide Fragments/pharmacology , Platelet Activating Factor/pharmacology , Proto-Oncogene Proteins/metabolism , Receptors, G-Protein-Coupled/metabolism , SARS-CoV-2 , Sex Distribution , Sex Factors , Up-Regulation , Young Adult
10.
J Agric Food Chem ; 68(49): 14402-14408, 2020 Dec 09.
Article in English | MEDLINE | ID: covidwho-1023816

ABSTRACT

IRW (Ile-Arg-Trp) was identified as an inhibitor of angiotensin converting enzyme (ACE) from egg white protein ovotransferrin through an integrated in silico digestion and quantitative structure and activity relationship prediction in 2011. Oral administration of IRW to spontaneously hypertensive rats (SHRs) can significantly reduce blood pressure, via upregulation of ACE2, but not through the inhibition of ACE. ACE2 converts Ang II into Ang (1-7), thus lowering blood pressure via Mas receptor (MasR); coinfusion of Mas receptor antagonist A779 and IRW in SHRs abolished blood pressure-lowering effect of IRW, supporting a key role of ACE2/Ang (1-7)/MasR axis. Our ongoing study further established new roles of IRW as an antioxidant, an anti-inflammatory agent, an insulin sensitizer, and a bone cell anabolic. Future studies are warranted to understand the unique structure features of this peptide, its mechanisms of action at various targets, its bioavailability and metabolism, and its possible roles toward COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Conalbumin/pharmacology , Enzyme Activators/pharmacology , Oligopeptides/pharmacology , Peptide Fragments/pharmacology , Animals , Cell Line , Conalbumin/therapeutic use , Enzyme Activators/therapeutic use , Humans , Oligopeptides/therapeutic use , Peptide Fragments/therapeutic use , SARS-CoV-2/metabolism , Virus Attachment
11.
Bioconjug Chem ; 32(1): 215-223, 2021 01 20.
Article in English | MEDLINE | ID: covidwho-997757

ABSTRACT

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a novel and highly pathogenic coronavirus and is the causative agent of the coronavirus disease 2019 (COVID-19). The high morbidity and mortality associated with COVID-19 and the lack of an approved drug or vaccine for SARS-CoV-2 underscores the urgent need for developing effective antiviral therapies. Therapeutics that target essential viral proteins are effective at controlling virus replication and spread. Coronavirus Spike glycoproteins mediate viral entry and fusion with the host cell, and thus are essential for viral replication. To enter host cells, the Spike proteins of SARS-CoV-2 and related coronavirus, SARS-CoV, bind the host angiotensin-converting enzyme 2 (ACE2) receptor through their receptor binding domains (RBDs). Here, we rationally designed a panel of ACE2-derived peptides based on the RBD-ACE2 binding interfaces of SARS-CoV-2 and SARS-CoV. Using SARS-CoV-2 and SARS-CoV Spike-pseudotyped viruses, we found that a subset of peptides inhibits Spike-mediated infection with IC50 values in the low millimolar range. We identified two peptides that bound Spike RBD in affinity precipitation assays and inhibited infection with genuine SARS-CoV-2. Moreover, these peptides inhibited the replication of a common cold causing coronavirus, which also uses ACE2 as its entry receptor. Results from the infection experiments and modeling of the peptides with Spike RBD identified a 6-amino-acid (Glu37-Gln42) ACE2 motif that is important for SARS-CoV-2 inhibition. Our work demonstrates the feasibility of inhibiting SARS-CoV-2 with peptide-based inhibitors. These findings will allow for the successful development of engineered peptides and peptidomimetic-based compounds for the treatment of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/chemistry , Antiviral Agents/pharmacology , Drug Design , Peptide Fragments/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/metabolism , HEK293 Cells , Humans , Molecular Docking Simulation , Peptide Fragments/metabolism , Protein Conformation , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
12.
Viruses ; 12(12)2020 11 30.
Article in English | MEDLINE | ID: covidwho-948866

ABSTRACT

SARS-CoV-2 infection is mediated by the binding of its spike protein to the angiotensin-converting enzyme 2 (ACE2), which plays a pivotal role in the renin-angiotensin system (RAS). The study of RAS dysregulation due to SARS-CoV-2 infection is fundamentally important for a better understanding of the pathogenic mechanisms and risk factors associated with COVID-19 coronavirus disease and to design effective therapeutic strategies. In this context, we developed a mathematical model of RAS based on data regarding protein and peptide concentrations; the model was tested on clinical data from healthy normotensive and hypertensive individuals. We used our model to analyze the impact of SARS-CoV-2 infection on RAS, which we modeled through a downregulation of ACE2 as a function of viral load. We also used it to predict the effect of RAS-targeting drugs, such as RAS-blockers, human recombinant ACE2, and angiotensin 1-7 peptide, on COVID-19 patients; the model predicted an improvement of the clinical outcome for some drugs and a worsening for others. Our model and its predictions constitute a valuable framework for in silico testing of hypotheses about the COVID-19 pathogenic mechanisms and the effect of drugs aiming to restore RAS functionality.


Subject(s)
COVID-19/pathology , Models, Theoretical , Renin-Angiotensin System/physiology , Angiotensin I/administration & dosage , Angiotensin I/pharmacology , Angiotensin Receptor Antagonists/administration & dosage , Angiotensin Receptor Antagonists/pharmacology , Angiotensin-Converting Enzyme 2/administration & dosage , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/pharmacology , COVID-19/drug therapy , COVID-19/virology , Computer Simulation , Humans , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacology , Renin/antagonists & inhibitors , Renin-Angiotensin System/drug effects , SARS-CoV-2 , Viral Load
13.
Biochem Pharmacol ; 178: 114057, 2020 08.
Article in English | MEDLINE | ID: covidwho-378094

ABSTRACT

COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Drug Repositioning/methods , Neprilysin/antagonists & inhibitors , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Signal Transduction/drug effects , Angiotensin I/pharmacology , Angiotensin I/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/pharmacology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Drug Repositioning/statistics & numerical data , Drug Repositioning/trends , Humans , Neprilysin/metabolism , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , SARS-CoV-2
14.
Biomed J ; 43(4): 363-367, 2020 08.
Article in English | MEDLINE | ID: covidwho-306211

ABSTRACT

Background: The present study demonstrates the potential of flavanoid narcissoside against the novel corona virus (COVID-19) complications using molecular docking studies. Methods: The computation molecular docking screening was performed using Molegro Virtual Docker software (MVD) with grid resolution of 30 Å. Protein of COVID 19 virus was taken from protein data bank. Results: The standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide) identified from the protein inhibitor complex 6W63 from protein data bank was docked with COVID 19 protein 6W63 which showed MolDock score of -156.913, rerank Sore -121.296 and H Bond -5.7369, while the flavanoid narcissoside had showed MolDock score -180.739, Rerank Sore -137.092 and H Bond -18.6771. The narcissoside showed potent inhibitory effect which is greater than standard X77. The result showed that narcissoside have high affinity towards 6W63 as it showed thirteen hydrogen bonds with nine amino acids (Arg 188, Glu 166, His 164, Cys 145 (2 bonds), Asn 14 (2 bonds), Cys 44 (2 bonds), His 41 (2 bonds), Gln 192, Thr 190) while X777 showed four hydrogen bonds with amino acids (Gly 143, Cys 145, Glu 166, Ser 144). Conclusion: From computation approach it was concluded that narcissoside is a potent inhibitor of viral COVID 19 protein 6W63. The narcissoside have high affinity and inhibition potential than standard inhibitor X77 (N-(4-tert-butylphenyl)-N-[(1R)-2-(cyclohexylamino)-2-oxo-1-(pyridin-3-yl)ethyl]-1H-imidazole-4-carboxamide). The narcissoside predicted as more potent inhibitor which can be further optimize, pharmacologically and clinically evaluated for the treatment of novel coronavirus COVID-19.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Flavones/pharmacology , Molecular Docking Simulation , Pneumonia, Viral/drug therapy , COVID-19 , Flavones/chemistry , Humans , Molecular Docking Simulation/methods , Pandemics , Peptide Fragments/chemistry , Peptide Fragments/pharmacology , SARS-CoV-2
15.
Nat Commun ; 11(1): 2070, 2020 04 24.
Article in English | MEDLINE | ID: covidwho-116533

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, at the end of 2019, and there are currently no specific antiviral treatments or vaccines available. SARS-CoV-2 has been shown to use the same cell entry receptor as SARS-CoV, angiotensin-converting enzyme 2 (ACE2). In this report, we generate a recombinant protein by connecting the extracellular domain of human ACE2 to the Fc region of the human immunoglobulin IgG1. A fusion protein containing an ACE2 mutant with low catalytic activity is also used in this study. The fusion proteins are then characterized. Both fusion proteins have a high binding affinity for the receptor-binding domains of SARS-CoV and SARS-CoV-2 and exhibit desirable pharmacological properties in mice. Moreover, the fusion proteins neutralize virus pseudotyped with SARS-CoV or SARS-CoV-2 spike proteins in vitro. As these fusion proteins exhibit cross-reactivity against coronaviruses, they have potential applications in the diagnosis, prophylaxis, and treatment of SARS-CoV-2.


Subject(s)
Betacoronavirus/drug effects , Immunoglobulin Fc Fragments/chemistry , Immunoglobulin G/chemistry , Neutralization Tests , Peptidyl-Dipeptidase A/chemistry , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Angiotensin-Converting Enzyme 2 , Animals , Betacoronavirus/metabolism , Binding, Competitive/drug effects , Cross Reactions , Drug Design , Humans , Immunoglobulin Fc Fragments/metabolism , Immunoglobulin Fc Fragments/pharmacology , Immunoglobulin G/metabolism , Immunoglobulin G/pharmacology , In Vitro Techniques , Inhibitory Concentration 50 , Membrane Fusion/drug effects , Mice , Mice, Inbred BALB C , Mutation , Peptide Fragments/chemistry , Peptide Fragments/genetics , Peptide Fragments/metabolism , Peptide Fragments/pharmacology , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/pharmacokinetics , Peptidyl-Dipeptidase A/pharmacology , Protein Domains/genetics , Protein Stability , Receptors, Virus/antagonists & inhibitors , Receptors, Virus/chemistry , Receptors, Virus/genetics , Receptors, Virus/metabolism , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/pharmacokinetics , SARS Virus/drug effects , SARS Virus/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism
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