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1.
Science ; 383(6688): eadk6176, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38484056

RESUMEN

Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection. Transcriptomics data show that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. Our results offer promise for the further development of ODV to control outbreaks of filovirus disease more rapidly.


Asunto(s)
Alanina , Antivirales , Ebolavirus , Fiebre Hemorrágica Ebola , Nucleósidos , Profármacos , Animales , Administración Oral , Ebolavirus/efectos de los fármacos , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Fiebre Hemorrágica Ebola/prevención & control , Macaca fascicularis , Nucleósidos/administración & dosificación , Nucleósidos/farmacología , Adenosina Monofosfato/administración & dosificación , Adenosina Monofosfato/farmacología , Alanina/administración & dosificación , Alanina/análogos & derivados , Alanina/farmacología , Profármacos/administración & dosificación , Profármacos/farmacología , Antivirales/administración & dosificación , Antivirales/farmacología
2.
Antiviral Res ; 216: 105658, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37356729

RESUMEN

Remdesivir is a nucleotide prodrug with preclinical efficacy against lethal Nipah virus infection in African green monkeys when administered 1 day post inoculation (dpi) (Lo et al., 2019). Here, we determined whether remdesivir treatment was still effective when treatment administration initiation was delayed until 3 dpi. Three groups of six African green monkeys were inoculated with a lethal dose of Nipah virus, genotype Bangladesh. On 3 dpi, one group received a loading dose of 10 mg/kg remdesivir followed by daily dosing with 5 mg/kg for 11 days, one group received 10 mg/kg on 12 consecutive days, and the remaining group received an equivalent volume of vehicle solution. Remdesivir treatment initiation on 3 dpi provided partial protection from severe Nipah virus disease that was dose dependent, with 67% of animals in the high dose group surviving the challenge. However, remdesivir treatment did not prevent clinical disease, and surviving animals showed histologic lesions in the brain. Thus, early administration seems critical for effective remdesivir treatment during Nipah virus infection.


Asunto(s)
Infecciones por Henipavirus , Virus Nipah , Animales , Chlorocebus aethiops , Infecciones por Henipavirus/tratamiento farmacológico , Infecciones por Henipavirus/prevención & control , Encéfalo , Adenosina Monofosfato/farmacología , Adenosina Monofosfato/uso terapéutico , Alanina/farmacología , Alanina/uso terapéutico
3.
Antiviral Res ; 203: 105331, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35533777

RESUMEN

Yellow fever virus (YFV) continues to cause periodic outbreaks of severe disease throughout tropical regions of South America and Africa despite the availability of an effective vaccine. Despite efforts to control this virus for the last century, no antivirals have been approved for the treatment of YFV. The purpose of this study was to evaluate the broadly active antiviral compound remdesivir (RDV) in a hamster model of disease. Yellow fever (YF) disease in hamsters was prevented when treatment with RDV was initiated just prior to virus challenge, which was confirmed in a second study. Disease parameters including viremia, serum ALT and weight loss were significantly improved with RDV treatment in a dose-dependent manner. RDV was also effective when treatment was initiated as late as 4 days post-virus infection (dpi). These results demonstrate therapeutic efficacy of RDV in the treatment of YF in a relevant animal model of disease.


Asunto(s)
Vacuna contra la Fiebre Amarilla , Fiebre Amarilla , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Animales , Antivirales/uso terapéutico , Cricetinae , Viremia/tratamiento farmacológico , Fiebre Amarilla/prevención & control , Vacuna contra la Fiebre Amarilla/uso terapéutico , Virus de la Fiebre Amarilla
4.
JCI Insight ; 7(10)2022 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-35413016

RESUMEN

A major challenge in managing acute viral infections is ameliorating disease when treatment is delayed. Previously, we reported the success of a 2-pronged mAb and antiviral remdesivir therapeutic approach to treat advanced illness in rhesus monkeys infected with Marburg virus (MARV). Here, we explored the benefit of a similar combination therapy for Sudan ebolavirus (Sudan virus; SUDV) infection. Importantly, no licensed anti-SUDV therapeutics currently exist, and infection of rhesus macaques with SUDV results in a rapid disease course similar to MARV with a mean time to death of 8.3 days. When initiation of therapy with either remdesivir or a pan-ebolavirus mAb cocktail (MBP431) was delayed until 6 days after inoculation, only 20% of macaques survived. In contrast, when remdesivir and MBP431 treatment were combined beginning 6 days after inoculation, significant protection (80%) was achieved. Our results suggest that combination therapy may be a viable treatment for patients with advanced filovirus disease that warrants further clinical testing in future outbreaks.


Asunto(s)
Ebolavirus , Fiebre Hemorrágica Ebola , Marburgvirus , Virosis , Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Animales , Anticuerpos Monoclonales , Anticuerpos Antivirales , Fiebre Hemorrágica Ebola/tratamiento farmacológico , Fiebre Hemorrágica Ebola/prevención & control , Humanos , Macaca mulatta
5.
Nat Commun ; 12(1): 1891, 2021 03 25.
Artículo en Inglés | MEDLINE | ID: mdl-33767178

RESUMEN

Monoclonal antibodies (mAbs) and remdesivir, a small-molecule antiviral, are promising monotherapies for many viruses, including members of the genera Marburgvirus and Ebolavirus (family Filoviridae), and more recently, SARS-CoV-2. One of the major challenges of acute viral infections is the treatment of advanced disease. Thus, extending the window of therapeutic intervention is critical. Here, we explore the benefit of combination therapy with a mAb and remdesivir in a non-human primate model of Marburg virus (MARV) disease. While rhesus monkeys are protected against lethal infection when treatment with either a human mAb (MR186-YTE; 100%), or remdesivir (80%), is initiated 5 days post-inoculation (dpi) with MARV, no animals survive when either treatment is initiated alone beginning 6 dpi. However, by combining MR186-YTE with remdesivir beginning 6 dpi, significant protection (80%) is achieved, thereby extending the therapeutic window. These results suggest value in exploring combination therapy in patients presenting with advanced filovirus disease.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antivirales/uso terapéutico , Enfermedad del Virus de Marburg/tratamiento farmacológico , Marburgvirus/efectos de los fármacos , Adenosina Monofosfato/uso terapéutico , Alanina/uso terapéutico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada , Macaca mulatta , Enfermedad del Virus de Marburg/prevención & control , Carga Viral/efectos de los fármacos
6.
Angew Chem Int Ed Engl ; 58(5): 1437-1441, 2019 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-30537284

RESUMEN

Combination chemotherapy must strike a difficult balance between safety and efficacy. Current regimens suffer from poor therapeutic impact because drugs are given at their maximum tolerated dose (MTD), which compounds the toxicity risk and exposes tumors to non-optimal drug ratios. A modular framework has been developed that selectively delivers drug combinations at synergistic ratios via tumor-targeting aptamers for effective low-dose treatment. A nucleolin-recognizing aptamer was coupled to peptide scaffolds laden with precise ratios of doxorubicin (DOX) and camptothecin (CPT). This construct had an extremely low IC50 (31.9 nm) against MDA-MB-231 breast cancer cells in vitro, and exhibited in vivo efficacy at micro-dose injections (500 and 350 µg kg-1 dose-1 of DOX and CPT, respectively) that are 20-30-fold lower than their previously-reported MTDs. This approach represents a generalizable strategy for the safe and consistent delivery of combination drugs in oncology.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Aptámeros de Nucleótidos/química , Camptotecina/uso terapéutico , Doxorrubicina/uso terapéutico , Neoplasias/tratamiento farmacológico , Péptidos/química , Protocolos de Quimioterapia Combinada Antineoplásica/química , Camptotecina/química , Línea Celular , Proliferación Celular/efectos de los fármacos , Doxorrubicina/química , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Dosis Máxima Tolerada , Estructura Molecular , Neoplasias/patología
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