Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 20 de 22
Filter
1.
Molecules ; 27(5)2022 Feb 24.
Article in English | MEDLINE | ID: covidwho-1780062

ABSTRACT

Diseases caused by viruses are a global threat, resulting in serious medical and social problems for humanity. They are the main contributors to many minor and major outbreaks, epidemics, and pandemics worldwide. Over the years, medicinal plants have been used as a complementary treatment in a range of diseases. In this sense, this review addresses promising antiviral plants from Marajó island, a part of the Amazon region, which is known to present a very wide biodiversity of medicinal plants. The present review has been limited to articles and abstracts available in Scopus, Web of Science, Science Direct, Scielo, PubMed, and Google Scholar, as well as the patent offices in Brazil (INPI), United States (USPTO), Europe (EPO) and World Intellectual Property Organization (WIPO). As a result, some plants from Marajó island were reported to have actions against HIV-1,2, HSV-1,2, SARS-CoV-2, HAV and HBV, Poliovirus, and influenza. Our major conclusion is that plants of the Marajó region show promising perspectives regarding pharmacological potential in combatting future viral diseases.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Plant Extracts/chemistry , Plants, Medicinal/chemistry , Antiviral Agents/chemistry , Antiviral Agents/isolation & purification , Antiviral Agents/pharmacology , Brazil , COVID-19/virology , HIV-1/drug effects , Hepatitis A virus/drug effects , Herpesvirus 1, Human/drug effects , Humans , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Plants, Medicinal/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
2.
Molecules ; 27(1)2022 Jan 04.
Article in English | MEDLINE | ID: covidwho-1613911

ABSTRACT

When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502-8 µM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9-27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Glycyrrhizic Acid/chemistry , HIV Infections/drug therapy , HIV-1/drug effects , SARS-CoV-2/drug effects , Virus Replication , Animals , Antiviral Agents/chemical synthesis , COVID-19/virology , Chlorocebus aethiops , HIV Infections/virology , HeLa Cells , Humans , In Vitro Techniques , Vero Cells
3.
Viruses ; 14(1)2021 12 30.
Article in English | MEDLINE | ID: covidwho-1580401

ABSTRACT

Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC50 ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.


Subject(s)
Adenoviridae/drug effects , Antiviral Agents/pharmacology , Coronavirus/drug effects , HIV-1/drug effects , RNA Processing, Post-Transcriptional/drug effects , Thiazoles/pharmacology , Virus Replication/drug effects , Adenoviridae/physiology , Antiviral Agents/chemistry , Cell Line , Coronavirus/classification , Coronavirus/physiology , Gene Expression/drug effects , HIV-1/physiology , Humans , RNA Splicing Factors/metabolism , RNA, Viral/metabolism , Thiazoles/chemistry
4.
Viruses ; 13(10)2021 10 02.
Article in English | MEDLINE | ID: covidwho-1441885

ABSTRACT

Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.


Subject(s)
Antiviral Agents/pharmacology , Viral Protease Inhibitors/pharmacology , Viral Proteases/metabolism , Virus Diseases/drug therapy , Adenoviruses, Human/drug effects , Adenoviruses, Human/metabolism , Flavivirus/drug effects , Flavivirus/metabolism , HIV-1/drug effects , Herpesviridae/drug effects , Herpesviridae/metabolism , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Viral Proteases/biosynthesis
5.
Biomed Res Int ; 2021: 9998420, 2021.
Article in English | MEDLINE | ID: covidwho-1398744

ABSTRACT

The global burden of viral infection, especially the current pandemics of SARS-CoV-2, HIV/AIDS, and hepatitis, is a very risky one. Additionally, HCV expresses the necessity for antiviral therapeutic elements. Venoms are known to contain an array of bioactive peptides that are commonly used in the treatment of various medical issues. Several peptides isolated from scorpion venom have recently been proven to possess an antiviral activity against several viral families. The aim of this review is to provide an up-to-date overview of scorpion antiviral peptides and to discuss their modes of action and potential biomedical application against different viruses.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Peptides/pharmacology , Scorpion Venoms/chemistry , Virus Diseases/drug therapy , Animals , Coronavirus/drug effects , HIV-1/drug effects , Hepatitis Viruses/drug effects , Herpesvirus 1, Human/drug effects , Humans , Measles virus/drug effects , Peptides/chemistry , Peptides/isolation & purification , Virus Diseases/virology
6.
Molecules ; 25(12)2020 Jun 26.
Article in English | MEDLINE | ID: covidwho-1389454

ABSTRACT

Viruses can be spread from one person to another; therefore, they may cause disorders in many people, sometimes leading to epidemics and even pandemics. New, previously unstudied viruses and some specific mutant or recombinant variants of known viruses constantly appear. An example is a variant of coronaviruses (CoV) causing severe acute respiratory syndrome (SARS), named SARS-CoV-2. Some antiviral drugs, such as remdesivir as well as antiretroviral drugs including darunavir, lopinavir, and ritonavir are suggested to be effective in treating disorders caused by SARS-CoV-2. There are data on the utilization of antiretroviral drugs against SARS-CoV-2. Since there are many studies aimed at the identification of the molecular mechanisms of human immunodeficiency virus type 1 (HIV-1) infection and the development of novel therapeutic approaches against HIV-1, we used HIV-1 for our case study to identify possible molecular pathways shared by SARS-CoV-2 and HIV-1. We applied a text and data mining workflow and identified a list of 46 targets, which can be essential for the development of infections caused by SARS-CoV-2 and HIV-1. We show that SARS-CoV-2 and HIV-1 share some molecular pathways involved in inflammation, immune response, cell cycle regulation.


Subject(s)
Coronavirus Infections/epidemiology , Coronavirus Infections/metabolism , Data Mining/methods , HIV Infections/epidemiology , HIV Infections/metabolism , Host-Pathogen Interactions/immunology , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/metabolism , Anti-Inflammatory Agents/therapeutic use , Antigens, Differentiation/genetics , Antigens, Differentiation/immunology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Complement System Proteins/genetics , Complement System Proteins/immunology , Coronavirus Infections/drug therapy , Coronavirus Infections/immunology , Databases, Genetic , Gene Expression Regulation , HIV Infections/drug therapy , HIV Infections/immunology , HIV-1/drug effects , HIV-1/immunology , HIV-1/pathogenicity , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Humans , Immunity, Innate/drug effects , Immunologic Factors/therapeutic use , Inflammation , Interferons/genetics , Interferons/immunology , Interleukins/genetics , Interleukins/immunology , Metabolic Networks and Pathways/drug effects , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Repressor Proteins/genetics , Repressor Proteins/immunology , SARS-CoV-2 , Signal Transduction , Toll-Like Receptors/genetics , Toll-Like Receptors/immunology , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/immunology
7.
Acc Chem Res ; 54(17): 3349-3361, 2021 09 07.
Article in English | MEDLINE | ID: covidwho-1360179

ABSTRACT

Treatment of HIV-1 has largely involved targeting viral enzymes using a cocktail of inhibitors. However, resistance to these inhibitors and toxicity in the long term have pushed the field to identify new therapeutic targets. To that end, -1 programmed ribosomal frameshifting (-1 PRF) has gained attention as a potential node for therapeutic intervention. In this process, a ribosome moves one nucleotide backward in the course of translating a mRNA, revealing a new reading frame for protein synthesis. In HIV-1, -1 PRF allows the virus to regulate the ratios of enzymatic and structural proteins as needed for correct viral particle assembly. Two RNA structural elements are central to -1 PRF in HIV: a slippery sequence and a highly conserved stable hairpin called the HIV-1 frameshifting stimulatory signal (FSS). Dysregulation of -1 PRF is deleterious for the virus. Thus, -1 PRF is an attractive target for new antiviral development. It is important to note that HIV-1 is not the only virus exploiting -1 PRF for regulating production of its proteins. Coronaviruses, including the COVID-19 pandemic virus SARS-CoV-2, also rely on -1 PRF. In SARS-CoV-2 and other coronaviruses, -1 PRF is required for synthesis of RNA-dependent RNA polymerase and several other nonstructural proteins. Coronaviruses employ a more complex RNA structural element for regulating -1 PRF called a pseudoknot. The purpose of this Account is primarily to review the development of molecules targeting HIV-1 -1 PRF. These approaches are case studies illustrating how the entire pipeline from screening to the generation of high-affinity leads might be implemented. We consider both target-based and function-based screening, with a particular focus on our group's approach beginning with a resin-bound dynamic combinatorial library (RBDCL) screen. We then used rational design approaches to optimize binding affinity, selectivity, and cellular bioavailability. Our tactic is, to the best of our knowledge, the only study resulting in compounds that bind specifically to the HIV-1 FSS RNA and reduce infectivity of laboratory and drug-resistant strains of HIV-1 in human cells. Lessons learned from strategies targeting -1 PRF HIV-1 might provide solutions in the development of antivirals in areas of unmet medical need. This includes the development of new frameshift-altering therapies for SARS-CoV-2, approaches to which are very recently beginning to appear.


Subject(s)
Antiviral Agents/pharmacology , HIV-1/drug effects , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Combinatorial Chemistry Techniques , Frameshifting, Ribosomal/drug effects , Humans , Microbial Sensitivity Tests
9.
Dalton Trans ; 49(39): 13538-13543, 2020 Oct 12.
Article in English | MEDLINE | ID: covidwho-1305373

ABSTRACT

Lectins, which exhibit viral-interaction abilities, have garnered attention in the current pandemic era as potential neutralizing agents and vaccine candidates. Viral invasion through envelope proteins is modulated by N-linked glycosylation in the spike (S) protein. This study demonstrates the biophysical aspects between lectins and high-mannose and -galactose N-glycans to provide insights into binding events.


Subject(s)
Antiviral Agents/pharmacology , Concanavalin A/pharmacology , Polysaccharides/metabolism , Viral Envelope Proteins/metabolism , Coronavirus/drug effects , Coronavirus/physiology , Coronavirus Infections/drug therapy , HIV Infections/drug therapy , HIV-1/drug effects , HIV-1/physiology , Host-Pathogen Interactions/drug effects , Humans , Mannose/metabolism , Spike Glycoprotein, Coronavirus/metabolism
10.
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
11.
Molecules ; 26(5)2021 Mar 09.
Article in English | MEDLINE | ID: covidwho-1143539

ABSTRACT

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-(E)-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j, a hexadecyloxypropyl (HDP)/(isopropyloxycarbonyl-oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 µM, without significant cytotoxicity (IC50 = 66.4 µM in HepG2 cells, IC50 = 43.1 µM in HepG2 cells) at 10 µM.


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Azo Compounds/chemistry , Nucleosides/chemistry , Organophosphonates/chemistry , Prodrugs/chemical synthesis , Prodrugs/pharmacology , Alkenes/chemistry , Animals , Cell Line, Tumor , Chlorocebus aethiops , HIV-1/drug effects , Hepatitis B virus/drug effects , Humans , Magnetic Resonance Spectroscopy , Methylation , SARS-CoV-2/drug effects , Structure-Activity Relationship , Triazoles/chemistry , Vero Cells
12.
Artif Cells Nanomed Biotechnol ; 49(1): 204-218, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1109121

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a zoo tonic, highly pathogenic virus. The new type of coronavirus with contagious nature spread from Wuhan (China) to the whole world in a very short time and caused the new coronavirus disease (COVID-19). COVID-19 has turned into a global public health crisis due to spreading by close person-to-person contact with high transmission capacity. Thus, research about the treatment of the damages caused by the virus or prevention from infection increases everyday. Besides, there is still no approved and definitive, standardized treatment for COVID-19. However, this disaster experienced by human beings has made us realize the significance of having a system ready for use to prevent humanity from viral attacks without wasting time. As is known, nanocarriers can be targeted to the desired cells in vitro and in vivo. The nano-carrier system targeting a specific protein, containing the enzyme inhibiting the action of the virus can be developed. The system can be used by simple modifications when we encounter another virus epidemic in the future. In this review, we present a potential treatment method consisting of a nanoparticle-ribozyme conjugate, targeting ACE-2 receptors by reviewing the virus-associated ribozymes, their structures, types and working mechanisms.


Subject(s)
COVID-19/drug therapy , Nanoparticles/administration & dosage , RNA, Catalytic/therapeutic use , RNA, Viral/antagonists & inhibitors , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Clinical Trials as Topic , Drug Carriers , Drug Compounding , Drug Design , HIV Infections/drug therapy , HIV-1/drug effects , HIV-1/genetics , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/genetics , Models, Molecular , Nucleic Acid Conformation , RNA Interference , RNA, Catalytic/administration & dosage , RNA, Catalytic/chemistry , RNA, Catalytic/classification , RNA, Untranslated/classification , RNA, Untranslated/genetics , RNA, Untranslated/therapeutic use , Receptors, Coronavirus/antagonists & inhibitors , SARS Virus/drug effects , SARS Virus/genetics , SARS-CoV-2/genetics , SARS-CoV-2/physiology , Spike Glycoprotein, Coronavirus/physiology , Virus Replication/drug effects
13.
Viruses ; 13(1)2021 Jan 16.
Article in English | MEDLINE | ID: covidwho-1040133

ABSTRACT

HIV-1 subtype CRF01_AE is the second most predominant strain in Bulgaria, yet little is known about the molecular epidemiology of its origin and transmissibility. We used a phylodynamics approach to better understand this sub-epidemic by analyzing 270 HIV-1 polymerase (pol) sequences collected from persons diagnosed with HIV/AIDS between 1995 and 2019. Using network analyses at a 1.5% genetic distance threshold (d), we found a large 154-member outbreak cluster composed mostly of persons who inject drugs (PWID) that were predominantly men. At d = 0.5%, which was used to identify more recent transmission, the large cluster dissociated into three clusters of 18, 12, and 7 members, respectively, five dyads, and 107 singletons. Phylogenetic analysis of the Bulgarian sequences with publicly available global sequences showed that CRF01_AE likely originated from multiple Asian countries, with Vietnam as the likely source of the outbreak cluster between 1988 and 1990. Our findings indicate that CRF01_AE was introduced into Bulgaria multiple times since 1988, and infections then rapidly spread among PWID locally with bridging to other risk groups and countries. CRF01_AE continues to spread in Bulgaria as evidenced by the more recent large clusters identified at d = 0.5%, highlighting the importance of public health prevention efforts in the PWID communities.


Subject(s)
Genotype , HIV Infections/epidemiology , HIV Infections/transmission , HIV Infections/virology , HIV-1/classification , HIV-1/genetics , Adolescent , Adult , Aged , Bulgaria/epidemiology , Female , Genetic Variation , HIV Infections/prevention & control , HIV-1/drug effects , Humans , Male , Middle Aged , Molecular Epidemiology , Phylogeny , Phylogeography , Public Health Surveillance , Reassortant Viruses , Recombination, Genetic , Young Adult
14.
Infect Control Hosp Epidemiol ; 42(3): 253-260, 2021 03.
Article in English | MEDLINE | ID: covidwho-1009986

ABSTRACT

BACKGROUND: Personal protective equipment (PPE) is a critical need during the coronavirus disease 2019 (COVID-19) pandemic. Alternative sources of surgical masks, including 3-dimensionally (3D) printed approaches that may be reused, are urgently needed to prevent PPE shortages. Few data exist identifying decontamination strategies to inactivate viral pathogens and retain 3D-printing material integrity. OBJECTIVE: To test viral disinfection methods on 3D-printing materials. METHODS: The viricidal activity of common disinfectants (10% bleach, quaternary ammonium sanitizer, 3% hydrogen peroxide, or 70% isopropanol and exposure to heat (50°C, and 70°C) were tested on four 3D-printed materials used in the healthcare setting, including a surgical mask design developed by the Veterans' Health Administration. Inactivation was assessed for several clinically relevant RNA and DNA pathogenic viruses, including severe acute respiratory coronavirus virus 2 (SARS-CoV-2) and human immunodeficiency virus 1 (HIV-1). RESULTS: SARS-CoV-2 and all viruses tested were completely inactivated by a single application of bleach, ammonium quaternary compounds, or hydrogen peroxide. Similarly, exposure to dry heat (70°C) for 30 minutes completely inactivated all viruses tested. In contrast, 70% isopropanol reduced viral titers significantly less well following a single application. Inactivation did not interfere with material integrity of the 3D-printed materials. CONCLUSIONS: Several standard decontamination approaches effectively disinfected 3D-printed materials. These approaches were effective in the inactivation SARS-CoV-2, its surrogates, and other clinically relevant viral pathogens. The decontamination of 3D-printed surgical mask materials may be useful during crisis situations in which surgical mask supplies are limited.


Subject(s)
COVID-19/prevention & control , Disinfectants/pharmacology , Disinfection/methods , Masks , SARS-CoV-2/drug effects , Virus Inactivation , 2-Propanol , DNA, Viral/drug effects , Decontamination/methods , HIV-1/drug effects , Healthy Volunteers , Hot Temperature , Humans , Hydrogen Peroxide , Personal Protective Equipment , Printing, Three-Dimensional , RNA, Viral/drug effects , Virus Diseases/prevention & control
16.
Viruses ; 13(1)2020 12 30.
Article in English | MEDLINE | ID: covidwho-1004763

ABSTRACT

P-selectin glycoprotein ligand-1 (PSGL-1) is a cell surface glycoprotein that binds to P-, E-, and L-selectins to mediate the tethering and rolling of immune cells on the surface of the endothelium for cell migration into inflamed tissues. PSGL-1 has been identified as an interferon-γ (INF-γ)-regulated factor that restricts HIV-1 infectivity, and has recently been found to possess broad-spectrum antiviral activities. Here we report that the expression of PSGL-1 in virus-producing cells impairs the incorporation of SARS-CoV and SARS-CoV-2 spike (S) glycoproteins into pseudovirions and blocks pseudovirus attachment and infection of target cells. These findings suggest that PSGL-1 may potentially inhibit coronavirus replication in PSGL-1+ cells.


Subject(s)
COVID-19/virology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/metabolism , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/drug effects , Virion , Animals , Cell Line , HEK293 Cells , HIV-1/drug effects , Humans , Interferon-gamma , Virus Attachment/drug effects , Virus Internalization/drug effects
17.
Sci Rep ; 10(1): 20397, 2020 11 23.
Article in English | MEDLINE | ID: covidwho-940864

ABSTRACT

COVID-19 caused by the SARS-CoV-2 is a current global challenge and urgent discovery of potential drugs to combat this pandemic is a need of the hour. 3-chymotrypsin-like cysteine protease (3CLpro) enzyme is the vital molecular target against the SARS-CoV-2. Therefore, in the present study, 1528 anti-HIV1compounds were screened by sequence alignment between 3CLpro of SARS-CoV-2 and avian infectious bronchitis virus (avian coronavirus) followed by machine learning predictive model, drug-likeness screening and molecular docking, which resulted in 41 screened compounds. These 41 compounds were re-screened by deep learning model constructed considering the IC50 values of known inhibitors which resulted in 22 hit compounds. Further, screening was done by structural activity relationship mapping which resulted in two structural clefts. Thereafter, functional group analysis was also done, where cluster 2 showed the presence of several essential functional groups having pharmacological importance. In the final stage, Cluster 2 compounds were re-docked with four different PDB structures of 3CLpro, and their depth interaction profile was analyzed followed by molecular dynamics simulation at 100 ns. Conclusively, 2 out of 1528 compounds were screened as potential hits against 3CLpro which could be further treated as an excellent drug against SARS-CoV-2.


Subject(s)
Anti-HIV Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Cheminformatics/methods , Deep Learning , Drug Repositioning/methods , HIV-1/drug effects , Molecular Dynamics Simulation , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , COVID-19/virology , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Evaluation, Preclinical/methods , Humans , Infectious bronchitis virus/drug effects , Molecular Docking Simulation , SARS-CoV-2/enzymology
18.
J Am Chem Soc ; 142(40): 17024-17038, 2020 10 07.
Article in English | MEDLINE | ID: covidwho-772998

ABSTRACT

Broad-spectrum antivirals are powerful weapons against dangerous viruses where no specific therapy exists, as in the case of the ongoing SARS-CoV-2 pandemic. We discovered that a lysine- and arginine-specific supramolecular ligand (CLR01) destroys enveloped viruses, including HIV, Ebola, and Zika virus, and remodels amyloid fibrils in semen that promote viral infection. Yet, it is unknown how CLR01 exerts these two distinct therapeutic activities. Here, we delineate a novel mechanism of antiviral activity by studying the activity of tweezer variants: the "phosphate tweezer" CLR01, a "carboxylate tweezer" CLR05, and a "phosphate clip" PC. Lysine complexation inside the tweezer cavity is needed to antagonize amyloidogenesis and is only achieved by CLR01. Importantly, CLR01 and CLR05 but not PC form closed inclusion complexes with lipid head groups of viral membranes, thereby altering lipid orientation and increasing surface tension. This process disrupts viral envelopes and diminishes infectivity but leaves cellular membranes intact. Consequently, CLR01 and CLR05 display broad antiviral activity against all enveloped viruses tested, including herpesviruses, Measles virus, influenza, and SARS-CoV-2. Based on our mechanistic insights, we potentiated the antiviral, membrane-disrupting activity of CLR01 by introducing aliphatic ester arms into each phosphate group to act as lipid anchors that promote membrane targeting. The most potent ester modifications harbored unbranched C4 units, which engendered tweezers that were approximately one order of magnitude more effective than CLR01 and nontoxic. Thus, we establish the mechanistic basis of viral envelope disruption by specific tweezers and establish a new class of potential broad-spectrum antivirals with enhanced activity.


Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Bridged-Ring Compounds/pharmacology , Organophosphates/pharmacology , Viral Envelope Proteins/drug effects , Acid Phosphatase/chemistry , Acid Phosphatase/metabolism , Amyloid/antagonists & inhibitors , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Arginine/chemistry , Betacoronavirus/drug effects , Bridged-Ring Compounds/chemistry , Cell Membrane/chemistry , Cell Membrane/drug effects , Cell Membrane/virology , HIV Infections/drug therapy , HIV-1/drug effects , Humans , Lipids/chemistry , Lysine/chemistry , Magnetic Resonance Spectroscopy , Organophosphates/chemistry , SARS-CoV-2 , Seminal Vesicle Secretory Proteins/chemistry , Seminal Vesicle Secretory Proteins/metabolism , Structure-Activity Relationship , Viral Envelope Proteins/metabolism , Zika Virus/drug effects
19.
Sci Adv ; 6(35): eaba7910, 2020 08.
Article in English | MEDLINE | ID: covidwho-760200

ABSTRACT

Targeting a universal host protein exploited by most viruses would be a game-changing strategy that offers broad-spectrum solution and rapid pandemic control including the current COVID-19. Here, we found a common YxxØ-motif of multiple viruses that exploits host AP2M1 for intracellular trafficking. A library chemical, N-(p-amylcinnamoyl)anthranilic acid (ACA), was identified to interrupt AP2M1-virus interaction and exhibit potent antiviral efficacy against a number of viruses in vitro and in vivo, including the influenza A viruses (IAVs), Zika virus (ZIKV), human immunodeficiency virus, and coronaviruses including MERS-CoV and SARS-CoV-2. YxxØ mutation, AP2M1 depletion, or disruption by ACA causes incorrect localization of viral proteins, which is exemplified by the failure of nuclear import of IAV nucleoprotein and diminished endoplasmic reticulum localization of ZIKV-NS3 and enterovirus-A71-2C proteins, thereby suppressing viral replication. Our study reveals an evolutionarily conserved mechanism of protein-protein interaction between host and virus that can serve as a broad-spectrum antiviral target.


Subject(s)
Adaptor Proteins, Vesicular Transport/metabolism , Antiviral Agents/pharmacology , Cinnamates/pharmacology , Coronavirus Infections/drug therapy , HIV Infections/drug therapy , Influenza, Human/drug therapy , Pneumonia, Viral/drug therapy , ortho-Aminobenzoates/pharmacology , A549 Cells , Animals , Betacoronavirus/drug effects , Binding Sites/genetics , COVID-19 , Cell Line, Tumor , Chlorocebus aethiops , Coronavirus Infections/pathology , Dogs , HEK293 Cells , HIV Infections/pathology , HIV-1/drug effects , Host-Pathogen Interactions/drug effects , Humans , Influenza A virus/drug effects , Influenza, Human/pathology , Madin Darby Canine Kidney Cells , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Middle East Respiratory Syndrome Coronavirus/drug effects , Pandemics , Pneumonia, Viral/pathology , Protein Binding/genetics , Protein Transport/drug effects , RNA, Viral/genetics , Receptor, Interferon alpha-beta/genetics , SARS-CoV-2 , Transforming Growth Factor beta1/metabolism , Vero Cells , Virus Replication/drug effects , Zika Virus/drug effects , Zika Virus Infection/pathology
20.
Curr Opin Struct Biol ; 65: 175-183, 2020 12.
Article in English | MEDLINE | ID: covidwho-752884

ABSTRACT

Many viruses, including Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Human Immunodeficiency Virus (HIV), use RNA as their genetic material. How viruses harness RNA structure and RNA-protein interactions to control their replication remains obscure. Recent advances in the characterization of HIV-1 reverse transcriptase, the enzyme that converts its single-stranded RNA genome into a double-stranded DNA copy, reveal how the reverse transcription complex evolves during initiation. Here we highlight these advances in HIV-1 structural biology and discuss how they are furthering our understanding of HIV and related ribonucleoprotein complexes implicated in viral disease.


Subject(s)
HIV-1/genetics , Reverse Transcription , Drug Design , HIV-1/drug effects , RNA, Transfer/genetics , Reverse Transcription/drug effects , Ribonucleases/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL