RESUMO
The 2013-2015 Ebola virus disease (EVD) epidemic is caused by the Makona variant of Ebola virus (EBOV). Early in the epidemic, genome sequencing provided insights into virus evolution and transmission and offered important information for outbreak response. Here, we analyze sequences from 232 patients sampled over 7 months in Sierra Leone, along with 86 previously released genomes from earlier in the epidemic. We confirm sustained human-to-human transmission within Sierra Leone and find no evidence for import or export of EBOV across national borders after its initial introduction. Using high-depth replicate sequencing, we observe both host-to-host transmission and recurrent emergence of intrahost genetic variants. We trace the increasing impact of purifying selection in suppressing the accumulation of nonsynonymous mutations over time. Finally, we note changes in the mucin-like domain of EBOV glycoprotein that merit further investigation. These findings clarify the movement of EBOV within the region and describe viral evolution during prolonged human-to-human transmission.
Assuntos
Ebolavirus/genética , Ebolavirus/isolamento & purificação , Genoma Viral , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/virologia , Mutação , Evolução Biológica , Surtos de Doenças , Ebolavirus/classificação , Doença pelo Vírus Ebola/transmissão , Humanos , Serra Leoa/epidemiologia , Manejo de EspécimesRESUMO
Remdesivir is a broad-spectrum antiviral nucleotide prodrug that has been clinically evaluated in Ebola virus patients and recently received emergency use authorization (EUA) for treatment of COVID-19. With approvals from the Federal Select Agent Program and the Centers for Disease Control and Prevention's Institutional Biosecurity Board, we characterized the resistance profile of remdesivir by serially passaging Ebola virus under remdesivir selection; we generated lineages with low-level reduced susceptibility to remdesivir after 35 passages. We found that a single amino acid substitution, F548S, in the Ebola virus polymerase conferred low-level reduced susceptibility to remdesivir. The F548 residue is highly conserved in filoviruses but should be subject to specific surveillance among novel filoviruses, in newly emerging variants in ongoing outbreaks, and also in Ebola virus patients undergoing remdesivir therapy. Homology modeling suggests that the Ebola virus polymerase F548 residue lies in the F-motif of the polymerase active site, a region that was previously identified as susceptible to resistance mutations in coronaviruses. Our data suggest that molecular surveillance of this region of the polymerase in remdesivir-treated COVID-19 patients is also warranted.
Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , Betacoronavirus/enzimologia , Ebolavirus/enzimologia , RNA Polimerase Dependente de RNA/química , Proteínas não Estruturais Virais/química , Monofosfato de Adenosina/farmacologia , Alanina/farmacologia , Betacoronavirus/química , Linhagem Celular , Tolerância a Medicamentos/genética , Ebolavirus/efeitos dos fármacos , Ebolavirus/genética , Humanos , Modelos Moleculares , Mutação , RNA Polimerase Dependente de RNA/genética , SARS-CoV-2 , Proteínas não Estruturais Virais/genética , Replicação Viral/efeitos dos fármacosRESUMO
OBJECTIVE: The purpose of this case series is to report on the effectiveness of a single percutaneous injection of doxycycline as a primary treatment for aneurysmal bone cyst (ABC). MATERIALS AND METHODS: A retrospective cohort study was conducted on seven patients diagnosed with ABC at various anatomical sites, with the intention to treat by a single percutaneous injection of doxycycline. Mean patient age was 14 years. RESULTS: Signs of treatment response were seen in six of seven patients after one injection. Three of the seven received a second treatment, despite signs of response. Another had expansion of the lesion after treatment, requiring excision. In total, three patients had a single injection of doxycycline as their sole treatment and another three showed signs of response after a single injection. CONCLUSIONS: A single percutaneous injection of doxycycline should be considered a viable primary treatment option for ABC.
Assuntos
Antibacterianos/administração & dosagem , Cistos Ósseos Aneurismáticos/diagnóstico por imagem , Cistos Ósseos Aneurismáticos/tratamento farmacológico , Doxiciclina/administração & dosagem , Adolescente , Feminino , Humanos , Injeções Intralesionais , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Due to their ability to inhibit viral DNA or RNA replication, nucleoside analogues have been used for decades as potent antiviral therapeutics. However, one of the major limitations of nucleoside analogues is the development of antiviral resistance. In that regard, flexible nucleoside analogues known as "fleximers" have garnered attention over the years due to their ability to survey different amino acids in enzyme binding sites, thus overcoming the potential development of antiviral resistance. Acyclic fleximers have previously demonstrated antiviral activity against numerous viruses including Middle East Respiratory Syndrome coronavirus (MERS-CoV), Ebola virus (EBOV), and, most recently, flaviviruses such as Dengue (DENV) and Yellow Fever Virus (YFV). Due to these interesting results, a Structure Activity Relationship (SAR) study was pursued in order to analyze the effect of the pyrimidine functional group and acyl protecting group on antiviral activity, cytotoxicity, and conformation. The results of those studies are presented herein.
Assuntos
Antivirais/química , Antivirais/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Ebolavirus/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Lipídeos/química , Conformação Molecular , Espectroscopia de Prótons por Ressonância Magnética , Relação Estrutura-AtividadeRESUMO
Fleximers, a novel type of flexible nucleoside that have garnered attention due to their unprecedented activity against human coronaviruses, have now exhibited highly promising levels of activity against filoviruses. The Flex-nucleoside was the most potent against recombinant Ebola virus in Huh7 cells with an EC50=2µM, while the McGuigan prodrug was most active against Sudan virus-infected HeLa cells with an EC50 of 7µM.
Assuntos
Antivirais/farmacologia , Ebolavirus/efeitos dos fármacos , Nucleosídeos/farmacologia , Antivirais/síntese química , Antivirais/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/síntese química , Nucleosídeos/química , Relação Estrutura-AtividadeRESUMO
During the Ebola virus outbreak of 2013-2016, the Viral Special Pathogens Branch field laboratory in Sierra Leone tested approximately 26 000 specimens between August 2014 and October 2015. Analysis of the B2M endogenous control Ct values showed its utility in monitoring specimen quality, comparing results with different specimen types, and interpretation of results. For live patients, blood is the most sensitive specimen type and oral swabs have little diagnostic utility. However, swabs are highly sensitive for diagnostic testing of corpses.
Assuntos
Surtos de Doenças , Ebolavirus/isolamento & purificação , Doença pelo Vírus Ebola/diagnóstico , RNA Viral/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Serviços de Laboratório Clínico , Ebolavirus/genética , Doença pelo Vírus Ebola/epidemiologia , Doença pelo Vírus Ebola/virologia , Humanos , Laboratórios , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sensibilidade e Especificidade , Serra Leoa/epidemiologiaRESUMO
To determine whether 2 readily available indicators predicted survival among patients with Ebola virus disease in Sierra Leone, we evaluated information for 216 of the 227 patients in Bo District during a 4-month period. The indicators were time from symptom onset to healthcare facility admission and quantitative real-time reverse transcription PCR cycle threshold (Ct), a surrogate for viral load, in first Ebola virus-positive blood sample tested. Of these patients, 151 were alive when detected and had reported healthcare facility admission dates and Ct values available. Time from symptom onset to healthcare facility admission was not associated with survival, but viral load in the first Ebola virus-positive blood sample was inversely associated with survival: 52 (87%) of 60 patients with a Ct of >24 survived and 20 (22%) of 91 with a Ct of <24 survived. Ct values may be useful for clinicians making treatment decisions or managing patient or family expectations.
Assuntos
Ebolavirus , Doença pelo Vírus Ebola/mortalidade , Doença pelo Vírus Ebola/virologia , Adolescente , Adulto , Feminino , Doença pelo Vírus Ebola/epidemiologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Vigilância da População , Prognóstico , Serra Leoa/epidemiologia , Adulto JovemRESUMO
In August 2014, the Viral Special Pathogens Branch of the US Centers for Disease Control and Prevention established a field laboratory in Sierra Leone in response to the ongoing Ebola virus outbreak. Through March 2015, this laboratory tested >12 000 specimens from throughout Sierra Leone. We describe the organization and procedures of the laboratory located in Bo, Sierra Leone.
Assuntos
Ebolavirus/isolamento & purificação , Doença pelo Vírus Ebola/diagnóstico , Doença pelo Vírus Ebola/virologia , Centers for Disease Control and Prevention, U.S. , Surtos de Doenças , Epidemias , Humanos , Laboratórios , Serra Leoa/epidemiologia , Estados UnidosRESUMO
No antiviral therapies are available for the tick-borne flaviviruses associated with hemorrhagic fevers: Kyasanur Forest disease virus (KFDV), both classical and the Alkhurma hemorrhagic fever virus (AHFV) subtype, and Omsk hemorrhagic fever virus (OHFV). We tested compounds reported to have antiviral activity against members of the Flaviviridae family for their ability to inhibit AHFV replication. 6-Azauridine (6-azaU), 2'-C-methylcytidine (2'-CMC), and interferon alpha 2a (IFN-α2a) inhibited the replication of AHFV and also KFDV, OHFV, and Powassan virus. The combination of IFN-α2a and 2'-CMC exerted an additive antiviral effect on AHFV, and the combination of IFN-α2a and 6-azaU was moderately synergistic. The combination of 2'-CMC and 6-azaU was complex, being strongly synergistic but with a moderate level of antagonism. The antiviral activity of 6-azaU was reduced by the addition of cytidine but not guanosine, suggesting that it acted by inhibiting pyrimidine biosynthesis. To investigate the mechanism of action of 2'-CMC, AHFV variants with reduced susceptibility to 2'-CMC were selected. We used a replicon system to assess the substitutions present in the selected AHFV population. A double NS5 mutant, S603T/C666S, and a triple mutant, S603T/C666S/M644V, were more resistant to 2'-CMC than the wild-type replicon. The S603T/C666S mutant had a reduced level of replication which was increased when M644V was also present, although the replication of this triple mutant was still below that of the wild type. The S603 and C666 residues were predicted to lie in the active site of the AHFV NS5 polymerase, implicating the catalytic center of the enzyme as the binding site for 2'-CMC.
Assuntos
Antivirais/farmacologia , Flavivirus/efeitos dos fármacos , Febres Hemorrágicas Virais/virologia , Doenças Transmitidas por Carrapatos/tratamento farmacológico , Doenças Transmitidas por Carrapatos/virologia , Substituição de Aminoácidos , Linhagem Celular , Citidina/análogos & derivados , Citidina/farmacologia , Efeito Citopatogênico Viral/efeitos dos fármacos , Farmacorresistência Viral , Flavivirus/genética , Humanos , Modelos Moleculares , Mutação/genética , Replicação Viral/efeitos dos fármacosRESUMO
Hantavirus pulmonary syndrome (HPS) is a severe respiratory disease characterized by pulmonary edema, with fatality rates of 35 to 45%. Disease occurs following infection with pathogenic New World hantaviruses, such as Andes virus (ANDV), which targets lung microvascular endothelial cells. During replication, the virus scavenges 5'-m(7)G caps from cellular mRNA to ensure efficient translation of viral proteins by the host cell cap-dependent translation machinery. In cells, the mammalian target of rapamycin (mTOR) regulates the activity of host cap-dependent translation by integrating amino acid, energy, and oxygen availability signals. Since there is no approved pharmacological treatment for HPS, we investigated whether inhibitors of the mTOR pathway could reduce hantavirus infection. Here, we demonstrate that treatment with the FDA-approved rapamycin analogue temsirolimus (CCI-779) blocks ANDV protein expression and virion release but not entry into primary human microvascular endothelial cells. This effect was specific to viral proteins, as temsirolimus treatment did not block host protein synthesis. We confirmed that temsirolimus targeted host mTOR complex 1 (mTORC1) and not a viral protein, as knockdown of mTORC1 and mTORC1 activators but not mTOR complex 2 components reduced ANDV replication. Additionally, primary fibroblasts from a patient with tuberous sclerosis exhibited increased mTORC1 activity and increased ANDV protein expression, which were blocked following temsirolimus treatment. Finally, we show that ANDV glycoprotein Gn colocalized with mTOR and lysosomes in infected cells. Together, these data demonstrate that mTORC1 signaling regulates ANDV replication and suggest that the hantavirus Gn protein may modulate mTOR and lysosomal signaling during infection, thus bypassing the cellular regulation of translation.
Assuntos
Complexos Multiproteicos/metabolismo , Orthohantavírus/patogenicidade , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Replicação Viral , Antivirais/farmacologia , Células Cultivadas , Técnicas de Silenciamento de Genes , Orthohantavírus/efeitos dos fármacos , Orthohantavírus/fisiologia , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina , Inibidores de Proteínas Quinases/farmacologia , Sirolimo/análogos & derivados , Sirolimo/farmacologiaRESUMO
There are no approved vaccines or therapeutics for Lassa virus (LASV) infections. To identify compounds with anti-LASV activity, we conducted a cell-based screening campaign at biosafety level 4 and tested almost 60,000 compounds for activity against an infectious reporter LASV. Hits from this screen included several structurally related macrocycles. The most potent, Mac128, had a sub-micromolar EC50 against the reporter virus, inhibited wild-type clade IV LASV, and reduced viral titers by 4 orders of magnitude. Mechanistic studies suggested that Mac128 inhibited viral replication at the level of the polymerase.
Assuntos
Antivirais , Vírus Lassa , Compostos Macrocíclicos , Replicação Viral , Vírus Lassa/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Replicação Viral/efeitos dos fármacos , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/química , Humanos , Animais , Chlorocebus aethiops , Células Vero , Febre Lassa/virologia , Febre Lassa/tratamento farmacológico , Linhagem Celular , Avaliação Pré-Clínica de Medicamentos , Proteínas Virais/antagonistas & inibidores , Proteínas Virais/metabolismo , Proteínas Virais/genéticaRESUMO
Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) is a novel human coronavirus that was identified in 2019. SARS-CoV-2 infection results in an acute, severe respiratory disease called coronavirus disease 2019 (COVID-19). The emergence and rapid spread of SARS-CoV-2 has led to a global public health crisis, which continues to affect populations across the globe. Real time reverse transcription polymerase chain reaction (rRT-PCR) is the reference standard test for COVID-19 diagnosis. Serological tests are valuable tools for serosurveillance programs and establishing correlates of protection from disease. This study evaluated the performance of one in-house enzyme linked immunosorbent assay (ELISA) utilizing the pre-fusion stabilized ectodomain of SARS-CoV-2 spike (S), two commercially available chemiluminescence assays Ortho VITROS Immunodiagnostic Products Anti-SARS-CoV-2 Total Reagent Pack and Abbott SARS-CoV-2 IgG assay and one commercially available Surrogate Virus Neutralization Test (sVNT), GenScript USA Inc., cPass SARS-CoV-2 Neutralization Antibody Detection Kit for the detection of SARS-CoV-2 specific antibodies. Using a panel of rRT-PCR confirmed COVID-19 patients' sera and a negative control group as a reference standard, all three immunoassays demonstrated high comparable positivity rates and low discordant rates. All three immunoassays were highly sensitive with estimated sensitivities ranging from 95.4-96.6â%. ROC curve analysis indicated that all three immunoassays had high diagnostic accuracies with area under the curve (AUC) values ranging from 0.9698 to 0.9807. High positive correlation was demonstrated among the conventional microneutralization test (MNT) titers and the sVNT inhibition percent values. Our study indicates that independent evaluations are necessary to optimize the overall utility and the interpretation of the results of serological tests. Overall, we demonstrate that all serological tests evaluated in this study are suitable for the detection of SARS-CoV-2 antibodies.
RESUMO
The Clostridium difficile toxins A and B are primarily responsible for symptoms of C. difficile associated disease and are prime targets for vaccine development. We describe a plasmid-based system for the production of genetically modified toxins in a non-sporulating strain of C. difficile that lacks the toxin genes tcdA and tcdB. TcdA and TcdB mutations targeting established glucosyltransferase cytotoxicity determinants were introduced into recombinant plasmids and episomally expressed toxin mutants purified from C. difficile transformants. TcdA and TcdB mutants lacking glucosyltransferase and autoproteolytic processing activities were ~10â000-fold less toxic to cultured human IMR-90 cells than corresponding recombinant or native toxins. However, both mutants retained residual cytotoxicity that could be prevented by preincubating the antigens with specific antibodies or by formalin treatment. Such non-toxic formalin-treated mutant antigens were immunogenic and protective in a hamster model of infection. The remaining toxicity of untreated TcdA and TcdB mutant antigens was associated with cellular swelling, a phenotype consistent with pore-induced membrane leakage. TcdB substitution mutations previously shown to block vesicular pore formation and toxin translocation substantially reduced residual toxicity. We discuss the implications of these results for the development of a C. difficile toxoid vaccine.
Assuntos
Vacinas Bacterianas/genética , Clostridioides difficile/imunologia , Infecções por Clostridium/prevenção & controle , Toxoides/genética , Vacinas Sintéticas/genética , Animais , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/genética , Toxinas Bacterianas/genética , Vacinas Bacterianas/administração & dosagem , Vacinas Bacterianas/imunologia , Linhagem Celular , Clostridioides difficile/genética , Infecções por Clostridium/imunologia , Infecções por Clostridium/microbiologia , Cricetinae , Enterocolite Pseudomembranosa/imunologia , Enterocolite Pseudomembranosa/microbiologia , Enterocolite Pseudomembranosa/prevenção & controle , Enterotoxinas/genética , Humanos , Mutação , Toxoides/administração & dosagem , Toxoides/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologiaRESUMO
Arenaviruses are highly pathogenic viruses that pose a serious public health threat. Chapare virus (CHAV) and Machupo virus (MACV), two New World arenaviruses, cause hemorrhagic fevers with case fatality rates of up to 45%. Research on therapeutic drug targets and vaccines for these viruses is limited because biosafety level 4 containment is required for handling them. In this study, we developed reverse genetics systems, including minigenomes and recombinant viruses, that will facilitate the study of these pathogens. The minigenome system is based on the S segment of CHAV or MACV genomes expressing the fluorescent reporter gene ZsGreen (ZsG). We also generated recombinant CHAV and MACV with and without the ZsG reporter gene. As a proof-of-concept study, we used both minigenomes and recombinant viruses to test the inhibitory effects of previously reported antiviral compounds. The new reverse genetics system described here will facilitate future therapeutic studies for these two life-threatening arenaviruses.
Assuntos
Arenavirus do Novo Mundo , Genética ReversaRESUMO
Seoul virus (SEOV) is an emerging global health threat that can cause hemorrhagic fever with renal syndrome (HFRS), which results in case fatality rates of â¼2%. There are no approved treatments for SEOV infections. We developed a cell-based assay system to identify potential antiviral compounds for SEOV and generated additional assays to characterize the mode of action of any promising antivirals. To test if candidate antivirals targeted SEOV glycoprotein-mediated entry, we developed a recombinant reporter vesicular stomatitis virus expressing SEOV glycoproteins. To facilitate the identification of candidate antiviral compounds targeting viral transcription/replication, we successfully generated the first reported minigenome system for SEOV. This SEOV minigenome (SEOV-MG) screening assay will also serve as a prototype assay for discovery of small molecules inhibiting replication of other hantaviruses, including Andes and Sin Nombre viruses. Ours is a proof-of-concept study in which we tested several compounds previously reported to have activity against other negative-strand RNA viruses using our newly developed hantavirus antiviral screening systems. These systems can be used under lower biocontainment conditions than those needed for infectious viruses, and identified several compounds with robust anti-SEOV activity. Our findings have important implications for the development of anti-hantavirus therapeutics.
Assuntos
Infecções por Hantavirus , Febre Hemorrágica com Síndrome Renal , Orthohantavírus , Vírus Seoul , Humanos , Orthohantavírus/genética , Vírus Seoul/genética , Seul , Proteínas Recombinantes , Glicoproteínas , Vesiculovirus/genéticaRESUMO
Candid1, a live-attenuated Junin virus vaccine strain, was developed during the early 1980s to control Argentine hemorrhagic fever, a severe and frequently fatal human disease. Six amino acid substitutions were found to be unique to this vaccine strain, and their role in virulence attenuation in mice was analyzed using a series of recombinant viruses. Our results indicate that Candid1 is attenuated in mice through a single amino acid substitution in the transmembrane domain of the G2 glycoprotein. This work provides insight into the molecular mechanisms of attenuation of the only arenavirus vaccine currently available.
Assuntos
Vírus Junin/imunologia , Vírus Junin/patogenicidade , Mutação de Sentido Incorreto , Proteínas do Envelope Viral/genética , Vacinas Virais/genética , Fatores de Virulência/genética , Substituição de Aminoácidos/genética , Animais , Infecções por Arenaviridae/patologia , Infecções por Arenaviridae/virologia , Análise Mutacional de DNA , Modelos Animais de Doenças , Camundongos , Dados de Sequência Molecular , Mutação Puntual , Doenças dos Roedores/patologia , Doenças dos Roedores/virologia , Análise de Sequência de DNA , Vacinas Atenuadas/genética , Vacinas Atenuadas/imunologia , Proteínas do Envelope Viral/metabolismo , Vacinas Virais/imunologia , Fatores de Virulência/metabolismoRESUMO
From July−November 2020, mink (Neogale vison) on 12 Utah farms experienced an increase in mortality rates due to confirmed SARS-CoV-2 infection. We conducted epidemiologic investigations on six farms to identify the source of virus introduction, track cross-species transmission, and assess viral evolution. Interviews were conducted and specimens were collected from persons living or working on participating farms and from multiple animal species. Swabs and sera were tested by SARS-CoV-2 real-time reverse transcription polymerase chain reaction (rRT-PCR) and serological assays, respectively. Whole genome sequencing was attempted for specimens with cycle threshold values <30. Evidence of SARS-CoV-2 infection was detected by rRT-PCR or serology in ≥1 person, farmed mink, dog, and/or feral cat on each farm. Sequence analysis showed high similarity between mink and human sequences on corresponding farms. On farms sampled at multiple time points, mink tested rRT-PCR positive up to 16 weeks post-onset of increased mortality. Workers likely introduced SARS-CoV-2 to mink, and mink transmitted SARS-CoV-2 to other animal species; mink-to-human transmission was not identified. Our findings provide critical evidence to support interventions to prevent and manage SARS-CoV-2 in people and animals on mink farms and emphasizes the importance of a One Health approach to address emerging zoonoses.
Assuntos
COVID-19 , Saúde Única , Animais , Humanos , Gatos , Cães , SARS-CoV-2/genética , COVID-19/epidemiologia , COVID-19/veterinária , Vison , Fazendas , Utah/epidemiologiaRESUMO
The necessity for intravenous administration of remdesivir confines its utility for treatment of coronavirus disease 2019 (COVID-19) to hospitalized patients. We evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524), against viruses that cause diseases of human public health concern, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). ODBG-P-RVn showed 20-fold greater antiviral activity than GS-441524 and had activity nearly equivalent to that of remdesivir in primary-like human small airway epithelial cells. Our results warrant in vivo efficacy evaluation of ODBG-P-RVn. IMPORTANCE While remdesivir remains one of the few drugs approved by the FDA to treat coronavirus disease 2019 (COVID-19), its intravenous route of administration limits its use to hospital settings. Optimizing the stability and absorption of remdesivir may lead to a more accessible and clinically potent therapeutic. Here, we describe an orally available lipid-modified version of remdesivir with activity nearly equivalent to that of remdesivir against emerging viruses that cause significant disease, including Ebola and Nipah viruses. Our work highlights the importance of such modifications to optimize drug delivery to relevant and appropriate human tissues that are most affected by such diseases.
Assuntos
Monofosfato de Adenosina/uso terapêutico , Adenosina/uso terapêutico , Alanina/uso terapêutico , Antivirais/uso terapêutico , Tratamento Farmacológico da COVID-19 , Nucleosídeos/uso terapêutico , Pró-Fármacos/uso terapêutico , Adenosina/análogos & derivados , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Éteres de Glicerila/uso terapêutico , Humanos , Lipídeos , SARS-CoV-2RESUMO
The intravenous administration of remdesivir for COVID-19 confines its utility to hospitalized patients. We evaluated the broad-spectrum antiviral activity of ODBG-P-RVn, an orally available, lipid-modified monophosphate prodrug of the remdesivir parent nucleoside (GS-441524) against viruses that cause diseases of human public health concern, including SARS-CoV-2. ODBG-P-RVn showed 20-fold greater antiviral activity than GS-441524 and had near-equivalent activity to remdesivir in primary-like human small airway epithelial cells. Our results warrant investigation of ODBG-P-RVn efficacy in vivo.
RESUMO
Lujo virus (LUJV), a highly pathogenic arenavirus, was first identified in 2008 in Zambia. To aid the identification of effective therapeutics for LUJV, we developed a recombinant reporter virus system, confirming reporter LUJV comparability with wild-type virus and its utility in high-throughput antiviral screening assays. Using this system, we evaluated compounds with known and unknown efficacy against related arenaviruses, with the aim of identifying LUJV-specific and potential new pan-arenavirus antivirals. We identified six compounds demonstrating robust anti-LUJV activity, including several compounds with previously reported activity against other arenaviruses. These data provide critical evidence for developing broad-spectrum antivirals against high-consequence arenaviruses.