RESUMEN
The discussion has revolved around the derivatives of amino acids and peptides containing carbocycles and their potential antiviral activity in vitro against influenza A, hepatitis C viruses, and coronavirus. Studies conducted on cell cultures reveal that aminoadamantane amino acid derivatives exhibit the capacity to hinder the replication of viruses containing viroporins. Furthermore, certain compounds demonstrate potent virucidal activity with respect to influenza A/H5N1 and hepatitis C virus particles. A conceptual framework for viroporin inhibitors has been introduced, incorporating carbocyclic motifs as membranotropic carriers in the structure, alongside a functional segment comprised of amino acids and peptides. These components correspond to the interaction with the inner surface of the channel's pore or another target protein.
Asunto(s)
Aminoácidos , Antivirales , Péptidos , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Humanos , Péptidos/farmacología , Péptidos/química , Péptidos/síntesis química , Aminoácidos/química , Aminoácidos/farmacología , Animales , Hepacivirus/efectos de los fármacos , Proteínas Viroporinas/antagonistas & inhibidores , Proteínas Viroporinas/metabolismo , Proteínas Viroporinas/química , Virus de la Influenza A/efectos de los fármacosRESUMEN
HIV-1 Vpu targets the host cell proteins CD4 and BST-2/Tetherin for degradation, ultimately resulting in enhanced virus spread and host immune evasion. The discovery and characterization of small molecules that antagonize Vpu would further elucidate the contribution of Vpu to pathogenesis and lay the foundation for the study of a new class of novel HIV-1 therapeutics. To identify novel compounds that block Vpu activity, we have developed a cell-based 'gain of function' assay that produces a positive signal in response to Vpu inhibition. To develop this assay, we took advantage of the viral glycoprotein, GaLV Env. In the presence of Vpu, GaLV Env is not incorporated into viral particles, resulting in non-infectious virions. Vpu inhibition restores infectious particle production. Using this assay, a high throughput screen of >650,000 compounds was performed to identify inhibitors that block the biological activity of Vpu. From this screen, we identified several positive hits but focused on two compounds from one structural family, SRI-41897 and SRI-42371. We developed independent counter-screens for off target interactions of the compounds and found no off target interactions. Additionally, these compounds block Vpu-mediated modulation of CD4, BST-2/Tetherin and antibody dependent cell-mediated toxicity (ADCC). Unfortunately, both SRI-41897 and SRI-42371 were shown to be specific to the N-terminal region of NL4-3 Vpu and did not function against other, more clinically relevant, strains of Vpu; however, this assay may be slightly modified to include more significant Vpu strains in the future.
Asunto(s)
Fármacos Anti-VIH , VIH-1 , Proteínas del Virus de la Inmunodeficiencia Humana , Proteínas Reguladoras y Accesorias Virales , Proteínas Viroporinas , Fármacos Anti-VIH/química , Antígeno 2 del Estroma de la Médula Ósea/metabolismo , Proteínas Ligadas a GPI/metabolismo , VIH-1/metabolismo , Proteínas del Virus de la Inmunodeficiencia Humana/antagonistas & inhibidores , Proteínas del Virus de la Inmunodeficiencia Humana/metabolismo , Virus de la Leucemia del Gibón/metabolismo , Bibliotecas de Moléculas Pequeñas , Proteínas Reguladoras y Accesorias Virales/antagonistas & inhibidores , Proteínas Reguladoras y Accesorias Virales/metabolismo , Proteínas Viroporinas/antagonistas & inhibidoresRESUMEN
The pandemic infectious disease (Covid-19) caused by the coronavirus (SARS-CoV2) is spreading rapidly around the world. Covid-19 does an irreparable harm to the health and life of people. It also has a negative financial impact on the economies of most countries of the world. In this regard, the issue of creating drugs aimed at combating this disease is especially acute. In this work, molecular docking was used to study the docking of 23 compounds with QRF3a SARS-CoV2. The performed in silico modeling made it possible to identify leading compounds capable of exerting a potential inhibitory and virucidal effect. The leading compounds include chlorin (a drug used in PDT), iron(III)protoporphyrin (endogenous porphyrin), and tetraanthraquinone porphyrazine (an exogenous substance). Having taken into consideration the localization of ligands in the QRF3a SARS-CoV2, we have made an assumption about their influence on the pathogenesis of Covid-19. The interaction of chlorin, iron(III)protoporphyrin and protoporphyrin with the viral protein ORF3a were studied by fluorescence and UV-Vis spectroscopy. The obtained experimental results confirm the data of molecular docking. The results showed that a viral protein binds to endogenous porphyrins and chlorins, moreover, chlorin is a competitive ligand for endogenous porphyrins. Chlorin should be considered as a promising drug for repurposing.
Asunto(s)
Antivirales/química , Antivirales/metabolismo , Compuestos Heterocíclicos/química , Compuestos Macrocíclicos/química , Compuestos Macrocíclicos/metabolismo , Proteínas Viroporinas/química , Proteínas Viroporinas/metabolismo , Sitios de Unión , Reposicionamiento de Medicamentos , Compuestos Heterocíclicos/metabolismo , Ligandos , Simulación del Acoplamiento Molecular , Porfirinas/química , Porfirinas/metabolismo , Protoporfirinas/química , Protoporfirinas/metabolismo , SARS-CoV-2/efectos de los fármacos , Proteínas Viroporinas/antagonistas & inhibidores , Tratamiento Farmacológico de COVID-19RESUMEN
Seasonal influenza A virus (IAV) infections are among the most important global health problems. FDA-approved antiviral therapies against IAV include neuraminidase inhibitors, M2 inhibitors, and polymerase inhibitor baloxavir. Resistance against adamantanes (amantadine and rimantadine) is widespread as virtually all IAV strains currently circulating in the human population are resistant to adamantanes through the acquisition of the S31N mutation. The neuraminidase inhibitor-resistant strains also contain the M2-S31N mutant, suggesting M2-S31N is a high-profile antiviral drug target. Here we report the development of a novel deuterium-containing M2-S31N inhibitor UAWJ280. UAWJ280 had broad-spectrum antiviral activity against both oseltamivir sensitive and -resistant influenza A strains and had a synergistic antiviral effect in combination with oseltamivir in cell culture. In vivo pharmacokinetic (PK) studies demonstrated that UAWJ280 had favourable PK properties. The in vivo mouse model study showed that UAWJ280 was effective alone or in combination with oseltamivir in improving clinical signs and survival after lethal challenge with an oseltamivir sensitive IAV H1N1 strain. Furthermore, UAWJ280 was also able to ameliorate clinical signs and increase survival when mice were challenged with an oseltamivir-resistant IAV H1N1 strain. In conclusion, we show for the first time that the M2-S31N channel blocker UAWJ280 has in vivo antiviral efficacy in mice that are infected with either oseltamivir sensitive or -resistant IAVs, and it has a synergistic antiviral effect with oseltamivir.
Asunto(s)
Anticuerpos Antivirales/sangre , Antivirales/farmacología , Antivirales/farmacocinética , Deuterio/química , Farmacorresistencia Viral , Virus de la Influenza A/efectos de los fármacos , Oseltamivir/farmacología , Proteínas de la Matriz Viral/antagonistas & inhibidores , Proteínas Viroporinas/antagonistas & inhibidores , Animales , Deuterio/farmacocinética , Deuterio/farmacología , Perros , Humanos , Virus de la Influenza A/clasificación , Células de Riñón Canino Madin Darby , Masculino , Ratones Endogámicos BALB C , Mutación , Infecciones por Orthomyxoviridae/tratamiento farmacológico , Infecciones por Orthomyxoviridae/virología , Relación Estructura-ActividadRESUMEN
SARS-CoV-2 ORF3a is a putative viral ion channel implicated in autophagy inhibition, inflammasome activation and apoptosis. 3a protein and anti-3a antibodies are found in infected patient tissues and plasma. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, suggesting it could be an effective target for vaccines or therapeutics. Here, we present structures of SARS-CoV-2 3a determined by cryo-EM to 2.1-Å resolution. 3a adopts a new fold with a polar cavity that opens to the cytosol and membrane through separate water- and lipid-filled openings. Hydrophilic grooves along outer helices could form ion-conduction paths. Using electrophysiology and fluorescent ion imaging of 3a-reconstituted liposomes, we observe Ca2+-permeable, nonselective cation channel activity, identify mutations that alter ion permeability and discover polycationic inhibitors of 3a activity. 3a-like proteins are found across coronavirus lineages that infect bats and humans, suggesting that 3a-targeted approaches could treat COVID-19 and other coronavirus diseases.
Asunto(s)
Microscopía por Crioelectrón , Nanoestructuras , SARS-CoV-2 , Proteínas Viroporinas/química , Proteínas Viroporinas/ultraestructura , Animales , Calcio/metabolismo , Quirópteros/virología , Coronaviridae , Electrofisiología , Fluorescencia , Humanos , Transporte Iónico , Liposomas , Modelos Moleculares , Nanoestructuras/química , Nanoestructuras/ultraestructura , Sistemas de Lectura Abierta , Imagen Óptica , Reproducibilidad de los Resultados , SARS-CoV-2/química , SARS-CoV-2/ultraestructura , Homología de Secuencia , Proteínas Virales/química , Proteínas Virales/ultraestructura , Proteínas Viroporinas/antagonistas & inhibidoresRESUMEN
The etiological agent of the COVID-19 pandemic is SARS-CoV-2. As a member of the Coronaviridae, the enveloped pathogen has several membrane proteins, of which two, E and 3a, were suggested to function as ion channels. In an effort to increase our treatment options, alongside providing new research tools, we have sought to inhibit the 3a channel by targeted drug repurposing. To that end, using three bacteria-based assays, we screened a library of 2839 approved-for-human-use drugs and identified the following potential channel-blockers: Capreomycin, Pentamidine, Spectinomycin, Kasugamycin, Plerixafor, Flumatinib, Litronesib, Darapladib, Floxuridine and Fludarabine. The stage is now set for examining the activity of these compounds in detailed electrophysiological studies and their impact on the whole virus with appropriate biosafety measures.
Asunto(s)
Antivirales/farmacología , COVID-19/virología , Reposicionamiento de Medicamentos , SARS-CoV-2/efectos de los fármacos , Proteínas del Envoltorio Viral/antagonistas & inhibidores , Proteínas del Envoltorio Viral/metabolismo , Proteínas Viroporinas/antagonistas & inhibidores , Proteínas Viroporinas/metabolismo , Evaluación Preclínica de Medicamentos , Humanos , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , Proteínas del Envoltorio Viral/genética , Proteínas Viroporinas/genética , Tratamiento Farmacológico de COVID-19RESUMEN
The COVID-19 epidemic is one of the most influential epidemics in history. Understanding the impact of coronaviruses (CoVs) on host cells is very important for disease treatment. The SARS-CoV-2 envelope (E) protein is a small structural protein involved in many aspects of the viral life cycle. The E protein promotes the packaging and reproduction of the virus, and deletion of this protein weakens or even abolishes the virulence. This review aims to establish new knowledge by combining recent advances in the study of the SARS-CoV-2 E protein and by comparing it with the SARS-CoV E protein. The E protein amino acid sequence, structure, self-assembly characteristics, viroporin mechanisms and inhibitors are summarized and analyzed herein. Although the mechanisms of the SARS-CoV-2 and SARS-CoV E proteins are similar in many respects, specific studies on the SARS-CoV-2 E protein, for both monomers and oligomers, are still lacking. A comprehensive understanding of this protein should prompt further studies on the design and characterization of effective targeted therapeutic measures.
Asunto(s)
Antivirales/farmacología , Tratamiento Farmacológico de COVID-19 , Proteínas de la Envoltura de Coronavirus/antagonistas & inhibidores , Proteínas de la Envoltura de Coronavirus/metabolismo , SARS-CoV-2/fisiología , Secuencia de Aminoácidos , Animales , Antivirales/química , COVID-19/metabolismo , COVID-19/virología , Proteínas de la Envoltura de Coronavirus/química , Humanos , Modelos Moleculares , Conformación Proteica , SARS-CoV-2/química , SARS-CoV-2/efectos de los fármacos , Alineación de Secuencia , Proteínas Viroporinas/antagonistas & inhibidores , Proteínas Viroporinas/química , Proteínas Viroporinas/metabolismoRESUMEN
BIT225 is a first-in-class inhibitor of human immunodeficiency virus (HIV) type 1 Vpu. A phase II trial enrolled 36 HIV-1-infected, treatment-naive participants in Thailand to receive standard-of-care antiretroviral therapy (ART), tenofovir disoproxil fumarate/emtricitabine/efavirenz (Atripla), with 100 or 200 mg of BIT225 or placebo (daily) for 12 weeks. Combined treatment with BIT225 and ART was found to be generally safe and well tolerated, with antiviral efficacy comparable to that of ART alone. The secondary end point-soluble CD163, a marker of monocyte/macrophage inflammation-was noted to be significantly decreased in the BIT225 arm. Plasma-derived activated CD4+ and CD8+ T cells, natural killer cells, and interleukin 21 were increased in those treated with BIT225. These findings are consistent with inhibition of the known effects of HIV Vpu and may reflect clinically important modulation of inflammatory and immune function. Further clinical study is planned to both confirm and extend these important findings in treatment-naive, and treatment-experienced individuals. Clinical Trials Registration. Australian New Zealand Clinical Trials Registry (Universal Trial Number U1111-1191-2194).