RESUMO
Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4'-chloromethyl-2'-deoxy-2'-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4'-modified-2'-deoxy-2'-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.
Assuntos
Antivirais/síntese química , Desoxicitidina/análogos & derivados , Desoxirribonucleosídeos/síntese química , Pró-Fármacos/síntese química , Animais , Antivirais/farmacologia , Linhagem Celular Tumoral , Vírus Chikungunya/efeitos dos fármacos , Vírus Chikungunya/crescimento & desenvolvimento , Cricetulus , Vírus da Dengue/efeitos dos fármacos , Vírus da Dengue/crescimento & desenvolvimento , Desoxicitidina/síntese química , Desoxicitidina/farmacologia , Desoxirribonucleosídeos/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/virologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Testes de Sensibilidade Microbiana , Cultura Primária de Células , Pró-Fármacos/farmacologia , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/crescimento & desenvolvimento , Linfócitos T/efeitos dos fármacos , Linfócitos T/virologia , Falha de Tratamento , Replicação Viral/efeitos dos fármacos , Vírus do Nilo Ocidental/efeitos dos fármacos , Vírus do Nilo Ocidental/crescimento & desenvolvimento , Zika virus/efeitos dos fármacos , Zika virus/crescimento & desenvolvimentoRESUMO
INTRODUCTION: The burden of chronic hepatitis B virus (HBV) results in almost a million deaths per year. The most common treatment for chronic hepatitis B infection is long-term nucleoside analogs (NUC) or one-year interferon-alpha (pegylated or non-pegylated) therapy before or after NUC therapy. Unfortunately, these therapies rarely result in HBV functional cure because they do not eradicate HBV from the nucleus of the hepatocytes, where the covalently closed circular DNA (cccDNA) is formed and/or where the integrated HBV DNA persists in the host genome. Hence, the search continues for novel antiviral therapies that target different steps of the HBV replication cycle to cure chronically infected HBV individuals and eliminate HBV from the liver reservoirs. AREAS COVERED: The authors focus on capsid assembly modulators (CAMs). These molecules are unique because they impact not only one but several steps of HBV viral replication, including capsid assembly, capsid trafficking into the nucleus, reverse transcription, pre-genomic RNA (pgRNA), and polymerase protein co-packaging. EXPERT OPINION: Mono- or combination therapy, including CAMs with other HBV drugs, may potentially eliminate hepatitis B infections. Nevertheless, more data on their potential effect on HBV elimination is needed, especially when used daily for 6-12 months.
Assuntos
Hepatite B Crônica , Hepatite B , Humanos , Vírus da Hepatite B/genética , Capsídeo , Hepatite B Crônica/tratamento farmacológico , Antivirais/farmacologia , Antivirais/uso terapêutico , Hepatite B/tratamento farmacológico , Replicação Viral , DNA Circular/farmacologia , DNA Circular/uso terapêutico , DNA Viral/farmacologia , DNA Viral/uso terapêuticoRESUMO
More than 40 years into the pandemic, HIV remains a global burden and as of now, there is no cure in sight. Fortunately, highly active antiretroviral therapy (HAART) has been developed to manage and suppress HIV infection. Combinations of two to three drugs targeting key viral proteins, including compounds inhibiting HIV reverse transcriptase (RT), have become the cornerstone of HIV treatment. This review discusses nucleoside reverse transcriptase inhibitors (NRTIs), including chain terminators, delayed chain terminators, nucleoside reverse transcriptase translocation inhibitors (NRTTIs), and nucleotide competing RT inhibitors (NcRTIs); focusing on their history, mechanism of action, resistance, and current clinical application, including long-acting regimens.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/metabolismo , Humanos , Nucleosídeos/farmacologia , Nucleosídeos/uso terapêutico , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
Nucleoside analogs are the backbone of antiviral therapies. Drugs from this class undergo processing by host or viral kinases to form the active nucleoside triphosphate species that selectively inhibits the viral polymerase. It is the central hypothesis that the nucleoside triphosphate analog must be a favorable substrate for the viral polymerase and the nucleoside precursor must be a satisfactory substrate for the host kinases to inhibit viral replication. Herein, free energy perturbation (FEP) was used to predict substrate affinity for both host and viral enzymes. Several uridine 5'-monophosphate prodrug analogs known to inhibit hepatitis C virus (HCV) were utilized in this study to validate the use of FEP. Binding free energies to the host monophosphate kinase and viral RNA-dependent RNA polymerase (RdRp) were calculated for methyl-substituted uridine analogs. The 2'-C-methyl-uridine and 4'-C-methyl-uridine scaffolds delivered favorable substrate binding to the host kinase and HCV RdRp that were consistent with results from cellular antiviral activity in support of our new approach. In a prospective evaluation, FEP results suggest that 2'-C-dimethyl-uridine scaffold delivered favorable monophosphate and triphosphate substrates for both host kinase and HCV RdRp, respectively. Novel 2'-C-dimethyl-uridine monophosphate prodrug was synthesized and exhibited sub-micromolar inhibition of HCV replication. Using this novel approach, we demonstrated for the first time that nucleoside analogs can be rationally designed that meet the multi-target requirements for antiviral activity.
Assuntos
Hepatite C , Pró-Fármacos , Antivirais/metabolismo , Antivirais/farmacologia , Hepacivirus , Hepatite C/tratamento farmacológico , Humanos , Nucleosídeos/farmacologia , Nucleotídeos/farmacologia , Pró-Fármacos/farmacologia , RNA Polimerase Dependente de RNA , Uridina , Proteínas não Estruturais Virais , Replicação ViralRESUMO
We present a newly developed synthetic route to 2-bromo-2-fluoro ribolactone based on our published 2-chloro-2-fluoro ribolactone synthesis. Stereoselective fluorination is key to controlling the 2-diastereoselectivity. We also report a substantially improved glycosylation reaction with both the 2-bromo-2-fluoro and 2-chloro-2-fluoro sugars. These improvements allowed us to prepare 2'-dihalo nucleosides 13 and 14 in an overall 15-20% yield.
RESUMO
Coronavirus disease 2019 (COVID-19) is an emerging global pandemic with severe morbidity and mortality caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molnupiravir, an ester prodrug form of N4-hydroxycytidine (NHC), was recently emergency-use approved for the treatment of early SARS-CoV-2 infections. Herein, we report the synthesis and evaluation of a series of novel NHC analogs.
RESUMO
Nipah virus (NiV) is a highly pathogenic zoonotic paramyxovirus that continues to cause outbreaks in humans characterized by high mortality and significant clinical sequelae in survivors. Currently, no therapeutics are approved for use in humans against NiV infection. Here, we report that 4'-chloromethyl-2'-deoxy-2'-fluorocytidine (ALS-8112) inhibits NiV. ALS-8112 is the parent nucleoside of lumicitabine, which has been evaluated in phase I and II clinical trials to treat pediatric and adult respiratory syncytial virus infection. In this study, we tested ALS-8112 against NiV and other major human respiratory pneumo- and paramyxoviruses in 2 human lung epithelial cell lines, and demonstrated the ability of ALS-8112 to reduce infectious wild-type NiV yield by over 6 orders of magnitude with no apparent cytotoxicity. However, further cytotoxicity testing in primary cells and bone marrow progenitor cells indicated cytotoxicity at higher concentrations of ALS-8112. Our results warrant the evaluation of lumicitabine against NiV infection in relevant animal models.
Assuntos
Antivirais/farmacologia , Desoxicitidina/análogos & derivados , Vírus Nipah/efeitos dos fármacos , Antivirais/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/química , Desoxicitidina/farmacologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/virologia , Células HeLa , Humanos , Pulmão/citologia , Nucleosídeos/química , Nucleosídeos/farmacologia , Paramyxoviridae/efeitos dos fármacosRESUMO
Hepatitis C virus (HCV) nucleoside inhibitors display pan-genotypic activity, a high barrier to the selection of resistant virus, and are some of the most potent direct-acting agents with durable sustained virologic response in humans. Herein, we report, the discovery of ß-d-2'-Br,2'-F-uridine phosphoramidate diastereomers 27 and 28, as nontoxic pan-genotypic anti-HCV agents. Extensive profiling of these two phosphorous diastereomers was performed to select one for in-depth preclinical profiling. The 5'-triphosphate formed from these phosphoramidates selectively inhibited HCV NS5B polymerase with no inhibition of human polymerases and cellular mitochondrial RNA polymerase up to 100 µM. Both are nontoxic by a variety of measures and display good stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes. Ultimately, a preliminary oral pharmacokinetics study in male beagles showed that 28 is superior to 27 and is an attractive candidate for further studies to establish its potential value as a new clinical anti-HCV agent.
Assuntos
Antivirais/farmacologia , Desoxirribonucleosídeos/farmacologia , Nucleotídeos de Desoxiuracil/farmacologia , Hepacivirus/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Antivirais/síntese química , Antivirais/farmacocinética , Linhagem Celular Tumoral , Desoxirribonucleosídeos/síntese química , Desoxirribonucleosídeos/farmacocinética , Nucleotídeos de Desoxiuracil/síntese química , Nucleotídeos de Desoxiuracil/farmacocinética , Cães , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Microssomos Hepáticos/metabolismo , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidoresRESUMO
A synthetic pathway to new acyclonucleoside phosphonates, as analogues of Adefovir, is described. The reduction of an acyclonucleoside ß-ketophosphonate, readily available from the nucleobase and benzylacrylate, afforded a mixture of (R)- and (S)-ß-hydroxyphosphonate derivatives which was resolved. The assignment of the absolute configuration was proposed on the basis of NMR studies and was supported by molecular modelling studies.