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1.
Sci Rep ; 12(1): 19114, 2022 Nov 09.
Article in English | MEDLINE | ID: covidwho-2106478

ABSTRACT

Fatty acids belong to a group of compounds already acknowledged for their broad antiviral efficacy. However, little is yet known about their effect on replication of human coronaviruses. To shed light on this subject, we first screened 15 fatty acids, three lipid-soluble vitamins, and cholesterol, on SARS-CoV-2 RdRp, and identified the four fatty acids with the highest RdRp inhibitory potential. Among them, linoleic acid was found to have the greatest interaction with SARS-CoV-2 RdRp, with its direct binding to the cavity formed by the RNA double helix and protein. Linoleic acid forms hydrophobic interactions with multiple residues, and at the same time forms electrostatic interactions including the hydrogen bond with Lys593 and Asp865. In line with these results, a dose-dependent inhibition of HCoV-OC43 replication in vitro was observed, additionally strengthened by data from in vivo study, which also confirmed anti-inflammatory potential of linoleic acid. Based on these results, we concluded that our study provides a new understanding of the antiviral properties of fatty acids against human coronaviruses including the SARS-CoV-2 strain. Particularly, they lays down a new prospect for linoleic acid's RdRp-inhibitory activity, as a candidate for further studies, which are warranted to corroborate the results presented here.


Subject(s)
COVID-19 , Coronavirus OC43, Human , Humans , SARS-CoV-2 , Linoleic Acid/pharmacology , Seasons , COVID-19/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , RNA-Dependent RNA Polymerase
2.
Cell ; 185(23): 4347-4360.e17, 2022 Nov 10.
Article in English | MEDLINE | ID: covidwho-2104495

ABSTRACT

Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here, we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5' end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analog inhibitors can be bonded to nsp9 and fit into a previously unknown "Nuc-pocket" in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an "induce-and-lock" mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs but also provide a strategy to design antiviral drugs.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase , Antiviral Agents/chemistry , Nucleotides/chemistry , Viral Nonstructural Proteins/metabolism
3.
J Mol Model ; 28(12): 380, 2022 Nov 07.
Article in English | MEDLINE | ID: covidwho-2103921

ABSTRACT

In response to the COVID-19 pandemic, and the lack of effective and safe antivirals against it, we adopted a new approach in which food supplements with vital antiviral characteristics, low toxicity, and fast excretion have been targeted. The structures and chemical properties of the food supplements were compared to the promising antivirals against SARS-COV-2. Our goal was to exploit the food supplements to mimic the topical antivirals' functions but circumventing their severe side effects, which has limited the necessary dosage needed to exhibit the desired antiviral activity. On this line, after a comparative structural analysis of the chemicals mentioned above, and investigation of their potential mechanisms of action, we selected caffeine and some compounds of the vitamin B family and further applied molecular modeling techniques to evaluate their interactions with the RDB domain of the Spike protein of SARS-CoV-2 (SC2Spike) and its corresponding binding site on human ACE-2 (HssACE2). Our results pointed to vitamins B1 and B6 in the neutral form as potential binders to the HssACE2 RDB binding pocket that might be able to impair the SARS-CoV-2 mechanism of cell invasion, qualifying as potential leads for experimental investigation against COVID-19.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , SARS-CoV-2 , Pyridoxamine , Thiamine/metabolism , Pandemics , Caffeine/pharmacology , Niacinamide , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Drug Design , Vitamins
4.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 39(5): 1005-1014, 2022 Oct 25.
Article in Chinese | MEDLINE | ID: covidwho-2100336

ABSTRACT

We aim to screen out the active components that may have therapeutic effect on coronavirus disease 2019 (COVID-19) from the severe and critical cases' prescriptions in the "Coronavirus Disease 2019 Diagnosis and Treatment Plan (Trial Ninth Edition)" issued by the National Health Commission of the People's Republic of China and explain its mechanism through the interactions with proteins. The ETCM database and SwissADME database were used to screen the active components contained in 25 traditional Chinese medicines in 3 prescriptions, and the PDB database was used to obtain the crystal structures of 4 proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular docking was performed using Autodock Vina and molecular dynamics simulations were performed using GROMACS. Binding energy results showed that 44 active ingredients including xambioona, gancaonin L, cynaroside, and baicalin showed good binding affinity with multiple targets of SARS-CoV-2, while molecular dynamics simulations analysis showed that xambioona bound more tightly to the nucleocapsid protein of SARS-CoV-2 and exerted a potent inhibitory effect. Modern technical methods are used to study the active components of traditional Chinese medicine and show that xambioona is an effective inhibitor of SARS-CoV-2 nucleocapsid protein, which provides a theoretical basis for the development of new anti-SARS-CoV-2 drugs and their treatment methods.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , SARS-CoV-2 , Molecular Docking Simulation , Medicine, Chinese Traditional , Molecular Dynamics Simulation , Nucleocapsid Proteins , Antiviral Agents/therapeutic use , Antiviral Agents/chemistry , Antiviral Agents/pharmacology
5.
Molecules ; 27(21)2022 Nov 04.
Article in English | MEDLINE | ID: covidwho-2099670

ABSTRACT

Since there is an urgent need for novel treatments to combat the current coronavirus disease 2019 (COVID-19) pandemic, in silico molecular docking studies were implemented as an attempt to explore the ability of selected bioactive constituents of extra virgin olive oil (EVOO) to act as potent SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antiviral compounds, aiming to explore their ability to interact with SARS-CoV-2 Spike key therapeutic target protein. Our results suggest that EVOO constituents display substantial capacity for binding and interfering with Spike (S) protein, both wild-type and mutant, via the receptor-binding domain (RBD) of Spike, or other binding targets such as angiotensin-converting enzyme 2 (ACE2) or the RBD-ACE2 protein complex, inhibiting the interaction of the virus with host cells. This in silico study provides useful insights for the understanding of the mechanism of action of the studied compounds at a molecular level. From the present study, it could be suggested that the studied active phytochemicals could potentially inhibit the Spike protein, contributing thus to the understanding of the role that they can play in future drug designing and the development of anti-COVID-19 therapeutics.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Olive Oil , Molecular Docking Simulation , COVID-19/drug therapy , Peptidyl-Dipeptidase A/metabolism , Binding Sites , Protein Binding
6.
Int J Mol Sci ; 23(21)2022 Nov 05.
Article in English | MEDLINE | ID: covidwho-2099579

ABSTRACT

Several human diseases are caused by viruses, including cancer, Type I diabetes, Alzheimer's disease, and hepatocellular carcinoma. In the past, people have suffered greatly from viral diseases such as polio, mumps, measles, dengue fever, SARS, MERS, AIDS, chikungunya fever, encephalitis, and influenza. Recently, COVID-19 has become a pandemic in most parts of the world. Although vaccines are available to fight the infection, their safety and clinical trial data are still questionable. Social distancing, isolation, the use of sanitizer, and personal productive strategies have been implemented to prevent the spread of the virus. Moreover, the search for a potential therapeutic molecule is ongoing. Based on experiences with outbreaks of SARS and MERS, many research studies reveal the potential of medicinal herbs/plants or chemical compounds extracted from them to counteract the effects of these viral diseases. COVID-19's current status includes a decrease in infection rates as a result of large-scale vaccination program implementation by several countries. But it is still very close and needs to boost people's natural immunity in a cost-effective way through phytomedicines because many underdeveloped countries do not have their own vaccination facilities. In this article, phytomedicines as plant parts or plant-derived metabolites that can affect the entry of a virus or its infectiousness inside hosts are described. Finally, it is concluded that the therapeutic potential of medicinal plants must be analyzed and evaluated entirely in the control of COVID-19 in cases of uncontrollable SARS infection.


Subject(s)
COVID-19 , Plants, Medicinal , Virus Diseases , Humans , COVID-19/drug therapy , COVID-19/epidemiology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Antiviral Agents/chemistry , SARS-CoV-2 , Disease Outbreaks/prevention & control , Virus Diseases/drug therapy , Plants, Medicinal/metabolism
7.
Biochemistry ; 61(22): 2495-2505, 2022 Nov 15.
Article in English | MEDLINE | ID: covidwho-2096611

ABSTRACT

The main protease (Mpro) of SARS-CoV-2 is essential for viral replication and has been the focus of many drug discovery efforts since the start of the COVID-19 pandemic. Nirmatrelvir (NTV) is an inhibitor of SARS-CoV-2 Mpro that is used in the combination drug Paxlovid for the treatment of mild to moderate COVID-19. However, with increased use of NTV across the globe, there is a possibility that future SARS-CoV-2 lineages will evolve resistance to NTV. Early prediction and monitoring of resistance mutations could allow for measures to slow the spread of resistance and for the development of new compounds with activity against resistant strains. In this work, we have used in silico mutational scanning and inhibitor docking of Mpro to identify potential resistance mutations. Subsequent in vitro experiments revealed five mutations (N142L, E166M, Q189E, Q189I, and Q192T) that reduce the potency of NTV and of a previously identified non-covalent cyclic peptide inhibitor of Mpro. The E166M mutation reduced the half-maximal inhibitory concentration (IC50) of NTV 24-fold and 118-fold for the non-covalent peptide inhibitor. Our findings inform the ongoing genomic surveillance of emerging SARS-CoV-2 lineages.


Subject(s)
Antiviral Agents , COVID-19 , Coronavirus 3C Proteases , Drug Resistance, Viral , Protease Inhibitors , SARS-CoV-2 , Humans , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/virology , Molecular Docking Simulation , Mutation , Pandemics , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , Drug Resistance, Viral/genetics , Coronavirus 3C Proteases/antagonists & inhibitors
8.
Antiviral Res ; 208: 105458, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2095047

ABSTRACT

Severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (Mpro), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 Mpro and SARS-CoV-2 Mpro and of rupintrivir in complex with SARS-CoV-2 Mpro were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC50 values of 47 µM and 101 µM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 Mpro. Equivalent IC50 values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 µM vs. 66 µM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Antiviral Agents/chemistry , COVID-19/drug therapy , Cysteine Endopeptidases/metabolism , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Molecular Docking Simulation
9.
Molecules ; 27(21)2022 Oct 29.
Article in English | MEDLINE | ID: covidwho-2090288

ABSTRACT

Chemical investigation of the total extract of the Egyptian soft coral Heteroxenia fuscescens, led to the isolation of eight compounds, including two new metabolites, sesquiterpene fusceterpene A (1) and a sterol fuscesterol A (4), along with six known compounds. The structures of 1-8 were elucidated via intensive studies of their 1D, 2D-NMR, and HR-MS analyses, as well as a comparison of their spectral data with those mentioned in the literature. Subsequent comprehensive in-silico-based investigations against almost all viral proteins, including those of the new variants, e.g., Omicron, revealed the most probable target for these isolated compounds, which was found to be Mpro. Additionally, the dynamic modes of interaction of the putatively active compounds were highlighted, depending on 50-ns-long MDS. In conclusion, the structural information provided in the current investigation highlights the antiviral potential of H. fuscescens metabolites with 3ß,5α,6ß-trihydroxy steroids with different nuclei against SARS-CoV-2, including newly widespread variants.


Subject(s)
Anthozoa , COVID-19 , Animals , SARS-CoV-2 , COVID-19/drug therapy , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Anthozoa/chemistry , Sterols , Molecular Docking Simulation , Molecular Dynamics Simulation
10.
Sci Rep ; 12(1): 17984, 2022 Oct 26.
Article in English | MEDLINE | ID: covidwho-2087304

ABSTRACT

Parallel cascade selection molecular dynamics-based ligand binding-path sampling (LB-PaCS-MD) was combined with fragment molecular orbital (FMO) calculations to reveal the ligand path from an aqueous solution to the SARS-CoV-2 main protease (Mpro) active site and to customise a ligand-binding pocket suitable for delivering a potent inhibitor. Rubraxanthone exhibited mixed-inhibition antiviral activity against SARS-CoV-2 Mpro, relatively low cytotoxicity, and high cellular inhibition. However, the atomic inhibition mechanism remains ambiguous. LB-PaCS-MD/FMO is a hybrid ligand-binding evaluation method elucidating how rubraxanthone interacts with SARS-CoV-2 Mpro. In the first step, LB-PaCS-MD, which is regarded as a flexible docking, efficiently samples a set of ligand-binding pathways. After that, a reasonable docking pose of LB-PaCS-MD is evaluated by the FMO calculation to elucidate a set of protein-ligand interactions, enabling one to know the binding affinity of a specified ligand with respect to a target protein. A possible conformation was proposed for rubraxanthone binding to the SARS-CoV-2 Mpro active site, and allosteric inhibition was elucidated by combining blind docking with k-means clustering. The interaction profile, key binding residues, and considerable interaction were elucidated for rubraxanthone binding to both Mpro sites. Integrated LB-PaCS-MD/FMO provided a more reasonable complex structure for ligand binding at the SARS-CoV-2 Mpro active site, which is vital for discovering and designing antiviral drugs.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Ligands , Protease Inhibitors/chemistry , COVID-19/drug therapy , Viral Nonstructural Proteins/metabolism , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Molecular Dynamics Simulation
11.
Antiviral Res ; 208: 105452, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2085918

ABSTRACT

SARS-CoV-2 is currently causing an unprecedented pandemic. While vaccines are massively deployed, we still lack effective large-scale antiviral therapies. In the quest for antivirals targeting conserved structures, we focused on molecules able to bind viral RNA secondary structures. Aminoglycosides are a class of antibiotics known to interact with the ribosomal RNA of both prokaryotes and eukaryotes and have previously been shown to exert antiviral activities by interacting with viral RNA. Here we show that the aminoglycoside geneticin is endowed with antiviral activity against all tested variants of SARS-CoV-2, in different cell lines and in a respiratory tissue model at non-toxic concentrations. The mechanism of action is an early inhibition of RNA replication and protein expression related to a decrease in the efficiency of the -1 programmed ribosomal frameshift (PRF) signal of SARS-CoV-2. Using in silico modeling, we have identified a potential binding site of geneticin in the pseudoknot of frameshift RNA motif. Moreover, we have selected, through virtual screening, additional RNA binding compounds, interacting with the same site with increased potency.


Subject(s)
COVID-19 , Frameshifting, Ribosomal , Humans , SARS-CoV-2/genetics , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , RNA, Viral/metabolism , COVID-19/drug therapy
12.
J Med Chem ; 64(24): 17601-17626, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-2084518

ABSTRACT

Nucleic acid aptamers are single-stranded DNA or RNA molecules selected in vitro that can bind to a broad range of targets with high affinity and specificity. As promising alternatives to conventional anti-infective agents, aptamers have gradually revealed their potential in the combat against infectious diseases. This article provides an overview on the state-of-art of aptamer-based antibacterial and antiviral therapeutic strategies. Diverse aptamers targeting pathogen-related components or whole pathogenic cells are summarized according to the species of microorganisms. These aptamers exhibited remarkable in vitro and/or in vivo inhibitory effect for pathogenic invasion, enzymatic activities, or viral replication, even for some highly drug-resistant strains and biofilms. Aptamer-mediated drug delivery and controlled drug release strategies are also included herein. Critical technical barriers of therapeutic aptamers are briefly discussed, followed by some future perspectives for their implementation into clinical utility.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Aptamers, Nucleotide/therapeutic use , Communicable Diseases/drug therapy , Animals , Anti-Bacterial Agents/chemistry , Antiviral Agents/chemistry , Aptamers, Nucleotide/chemistry , Biofilms , Humans , Structure-Activity Relationship
13.
Molecules ; 27(20)2022 Oct 17.
Article in English | MEDLINE | ID: covidwho-2071653

ABSTRACT

The tracing of an alternative drug, Phytochemicals is a promising approach to the viral threats that have emerged over the past two years. Across the world, herbal medicine is a better solution against anti-viral diseases during pandemic periods. Goniothalamus wightii is an herbal plant, which has diverse bioactive compounds with anticancer, antioxidant, and anti-viral properties. The aim of the study was to isolate the compound by chromatography studies and functionalization by FT-IR, LC-MS, and NMR (C-NMR, H-NMR). As a result, the current work focuses on whether (S)-Goniathalamin and its analogue could act as natural anti-viral molecules for multiple target proteins viz., MPro, RdRp, and SPro, which are required for SARS-CoV-2 infection. Overall, 954 compounds were examined and the molecular-docking studies were performed on the maestro platform of Schrodinger software. Molecular-dynamics simulation studies were performed on two complex major compounds to confirm their affinity across 150 simulations. This research suggests that plant-based drugs have high levels of antiviral properties against coronavirus. However, more research is needed to verify its antiviral properties.


Subject(s)
COVID-19 , Goniothalamus , Humans , SARS-CoV-2 , COVID-19/drug therapy , Coronavirus 3C Proteases , Antioxidants , Spectroscopy, Fourier Transform Infrared , Cysteine Endopeptidases/chemistry , Antiviral Agents/chemistry , Molecular Docking Simulation , Molecular Dynamics Simulation , RNA-Dependent RNA Polymerase
14.
Molecules ; 27(20)2022 Oct 12.
Article in English | MEDLINE | ID: covidwho-2071650

ABSTRACT

COVID-19 can cause different neurological symptoms in some people, including smell, inability to taste, dizziness, confusion, delirium, seizures, stroke, etc. Owing to the issue of vaccine effectiveness, update and coverage, we still need one or more diversified strategies as the backstop to manage illness. Characterizing the structural basis of ligand recognition in the main protease (Mpro) of SARS-CoV-2 will facilitate its rational design and development of potential drug candidates with high affinity and selectivity against COVID-19. Up to date, covalent-, non-covalent inhibitors and allosteric modulators have been reported to bind to different active sites of Mpro. In the present work, we applied the molecular dynamics (MD) simulations to systematically characterize the potential binding features of catalytic active site and allosteric binding sites in Mpro using a dataset of 163 3D structures of Mpro-inhibitor complexes, in which our results are consistent with the current studies. In addition, umbrella sampling (US) simulations were used to explore the dissociation processes of substrate pathway and allosteric pathway. All the information provided new insights into the protein features of Mpro and will facilitate its rational drug design for COVID-19.


Subject(s)
COVID-19 , Molecular Dynamics Simulation , Humans , SARS-CoV-2 , COVID-19/drug therapy , Ligands , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/metabolism , Coronavirus 3C Proteases , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
15.
Int J Mol Sci ; 23(20)2022 Oct 13.
Article in English | MEDLINE | ID: covidwho-2071505

ABSTRACT

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated the highest binding affinities towards SARS-CoV-2 Mpro. A molecular dynamics study at 200 ns was also carried out for the most promising anticoagulants to provide insights into the dynamic and thermodynamic properties of promising compounds. Moreover, a quantum mechanical study was also conducted which helped us to attest to some of the molecular docking and dynamics findings. A biological evaluation (in vitro) of the most promising compounds was also performed by carrying out the MTT cytotoxicity assay and the crystal violet assay in order to assess inhibitory concentration 50 (IC50). It is worth noting that ticagrelor displayed the highest intrinsic potential for the inhibition of SARS-CoV-2 with an IC50 value of 5.60 µM and a safety index of 25.33. In addition, fondaparinux sodium and dabigatran showed promising inhibitory activities with IC50 values of 8.60 and 9.40 µM, respectively, and demonstrated safety indexes of 17.60 and 15.10, respectively. Moreover, the inhibitory potential of the SARS-CoV-2 Mpro enzyme was investigated by utilizing the SARS-CoV-2 Mpro assay and using tipranavir as a reference standard. Interestingly, promising SARS-CoV-2 Mpro inhibitory potential was attained for fondaparinux sodium with an IC50 value of 2.36 µM, surpassing the reference tipranavir (IC50 = 7.38 µM) by more than three-fold. Furthermore, highly eligible SARS-CoV-2 Mpro inhibitory potential was attained for dabigatran with an IC50 value of 10.59 µM. Finally, an SAR was discussed, counting on the findings of both in vitro and in silico approaches.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/drug therapy , Molecular Docking Simulation , Coronavirus 3C Proteases , Molecular Dynamics Simulation , Fondaparinux , Anticoagulants/pharmacology , Anticoagulants/therapeutic use , Dabigatran , Ticagrelor , Eptifibatide , Gentian Violet , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/metabolism , Heparin/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/chemistry
16.
Eur J Med Chem ; 244: 114853, 2022 Dec 15.
Article in English | MEDLINE | ID: covidwho-2068912

ABSTRACT

SARS-CoV-2 caused worldwide the current outbreak called COVID-19. Despite multiple countermeasures implemented, there is an urgent global need for new potent and efficient antiviral drugs against this pathogen. In this context, the main protease (Mpro) of SARS-CoV-2 is an essential viral enzyme and plays a pivotal role in viral replication and transcription. Its specific cleavage of polypeptides after a glutamine residue has been considered as a key element to design novel antiviral drugs. Herein, we reported the design, synthesis and structure-activity relationships of novel α-ketoamides as covalent reversible inhibitors of Mpro, exploiting the PADAM oxidation route. The reported compounds showed µM to nM activities in enzymatic and in the antiviral cell-based assays against SARS-CoV-2 Mpro. In order to assess inhibitors' binding mode, two co-crystal structures of SARS-CoV-2 Mpro in complex with our inhibitors were solved, which confirmed the covalent binding of the keto amide moiety to the catalytic Cys145 residue of Mpro. Finally, in order to interrogate potential broad-spectrum properties, we assessed a selection of compounds against MERS Mpro where they showed nM inhibitory potency, thus highlighting their potential as broad-spectrum coronavirus inhibitors.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Coronavirus 3C Proteases , COVID-19/drug therapy , Protease Inhibitors/pharmacology , Protease Inhibitors/chemistry , Viral Nonstructural Proteins , Cysteine Endopeptidases/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Molecular Docking Simulation
17.
Viruses ; 14(10)2022 10 06.
Article in English | MEDLINE | ID: covidwho-2066559

ABSTRACT

Viruses are dependent on host factors in order to efficiently establish an infection and replicate. Targeting the interactions of such host factors provides an attractive strategy to develop novel antivirals. Syntenin is a protein known to regulate the architecture of cellular membranes by its involvement in protein trafficking and has previously been shown to be important for human papilloma virus (HPV) infection. Here, we show that a highly potent and metabolically stable peptide inhibitor that binds to the PDZ1 domain of syntenin inhibits severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by blocking the endosomal entry of the virus. Furthermore, we found that the inhibitor also hampered chikungunya infection and strongly reduced flavivirus infection, which is completely dependent on receptor-mediated endocytosis for their entry. In conclusion, we have identified a novel broad spectrum antiviral inhibitor that efficiently targets a broad range of RNA viruses.


Subject(s)
COVID-19 , RNA Viruses , Humans , SARS-CoV-2 , Syntenins , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Virus Internalization
18.
Viruses ; 14(10)2022 09 29.
Article in English | MEDLINE | ID: covidwho-2066548

ABSTRACT

In order to test the antiviral activity, a series of usnic acid derivatives were synthesized, including new, previously undescribed compounds. The activity of the derivatives against three strains of SARS-CoV-2 virus was studied. To understand the mechanism of antiviral action, the inhibitory activity of the main protease of SARS-CoV-2 virus was studied using the developed model as well as the antiviral activity against the pseudoviral system with glycoprotein S of SARS-CoV-2 virus on its surface. It was shown that usnic acid exhibits activity against three strains of SARS-CoV-2 virus: Wuhan, Delta, and Omicron. Compounds 10 and 13 also showed high activity against the three strains. The performed biological studies and molecular modeling allowed us to assume that the derivatives of usnic acid bind in the N-terminal domain of the surface glycoprotein S at the binding site of the hemoglobin decay metabolite.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , Protease Inhibitors/pharmacology , Molecular Docking Simulation , Antiviral Agents/pharmacology , Antiviral Agents/chemistry , Peptide Hydrolases , Membrane Glycoproteins
19.
Molecules ; 27(19)2022 Oct 09.
Article in English | MEDLINE | ID: covidwho-2066287

ABSTRACT

The main protease enzyme (Mpro) of SARS-CoV-2 is one of the most promising targets for COVID-19 treatment. Accordingly, in this work, a structure-based virtual screening of 3.8 million ligand libraries was carried out. After rigorous filtering, docking, and post screening assessments, 78 compounds were selected for biological evaluation, 3 of which showed promising inhibition of the Mpro enzyme. The obtained hits (CB03, GR04, and GR20) had reasonable potencies with Ki values in the medium to high micromolar range. Interestingly, while our most potent hit, GR20, was suggested to act via a reversible covalent mechanism, GR04 was confirmed as a noncompetitive inhibitor that seems to be one of a kind when compared to the other allosteric inhibitors discovered so far. Moreover, all three compounds have small sizes (~300 Da) with interesting fittings in their relevant binding sites, and they possess lead-like characteristics that can introduce them as very attractive candidates for the future development of COVID-19 treatments.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Catalytic Domain , Coronavirus 3C Proteases , Humans , Ligands , Molecular Docking Simulation , Protease Inhibitors/chemistry
20.
Molecules ; 27(19)2022 Oct 01.
Article in English | MEDLINE | ID: covidwho-2066282

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has stressed the global health system to a significant level, which has not only resulted in high morbidity and mortality but also poses a threat for future pandemics. This situation warrants efforts to develop novel therapeutics to manage SARS-CoV-2 in specific and other emerging viruses in general. This study focuses on SARS-CoV2 RNA-dependent RNA polymerase (RdRp) mutations collected from Saudi Arabia and their impact on protein structure and function. The Saudi SARS-CoV-2 RdRp sequences were compared with the reference Wuhan, China RdRp using a variety of computational and biophysics-based approaches. The results revealed that three mutations-A97V, P323I and Y606C-may affect protein stability, and hence the relationship of protein structure to function. The apo wild RdRp is more dynamically stable with compact secondary structure elements compared to the mutants. Further, the wild type showed stable conformational dynamics and interaction network to remdesivir. The net binding energy of wild-type RdRp with remdesivir is -50.76 kcal/mol, which is more stable than the mutants. The findings of the current study might deliver useful information regarding therapeutic development against the mutant RdRp, which may further furnish our understanding of SARS-CoV-2 biology.


Subject(s)
COVID-19 , SARS-CoV-2 , Antiviral Agents/chemistry , COVID-19/drug therapy , COVID-19/genetics , Humans , Molecular Docking Simulation , Mutation , Pandemics , Protein Binding , RNA, Viral/metabolism , RNA-Dependent RNA Polymerase/genetics , SARS-CoV-2/genetics , Saudi Arabia
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