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2.
Vaccines (Basel) ; 10(11)2022 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-36423030

RESUMO

Marburg virus (MARV) is a virus of high human consequence with a case fatality rate of 24-88%. The global health and national security risks posed by Marburg virus disease (MVD) underscore the compelling need for a prophylactic vaccine, but no candidate has yet reached regulatory approval. Here, we evaluate a replication-defective chimpanzee adenovirus type 3 (ChAd3)-vectored MARV Angola glycoprotein (GP)-expressing vaccine against lethal MARV challenge in macaques. The ChAd3 platform has previously been reported to protect against the MARV-related viruses, Ebola virus (EBOV) and Sudan virus (SUDV), and MARV itself in macaques, with immunogenicity demonstrated in macaques and humans. In this study, we present data showing 100% protection against MARV Angola challenge (versus 0% control survival) and associated production of GP-specific IgGs generated by the ChAd3-MARV vaccine following a single dose of 1 × 1011 virus particles prepared in a new clinical formulation buffer designed to enhance product stability. These results are consistent with previously described data using the same vaccine in a different formulation and laboratory, demonstrating the reproducible and robust protective efficacy elicited by this promising vaccine for the prevention of MVD. Additionally, a qualified anti-GP MARV IgG ELISA was developed as a critical pre-requisite for clinical advancement and regulatory approval.

3.
J Med Chem ; 59(5): 1891-8, 2016 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-26804933

RESUMO

Here, we describe the design, synthesis, biological evaluation, and identification of a clinical candidate non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a novel aryl-phospho-indole (APhI) scaffold. NNRTIs are recommended components of highly active antiretroviral therapy (HAART) for the treatment of HIV-1. Since a major problem associated with NNRTI treatment is the emergence of drug resistant virus, this work focused on optimization of the APhI against clinically relevant HIV-1 Y181C and K103N mutants and the Y181C/K103N double mutant. Optimization of the phosphinate aryl substituent led to the discovery of the 3-Me,5-acrylonitrile-phenyl analogue RP-13s (IDX899) having an EC50 of 11 nM against the Y181C/K103N double mutant.


Assuntos
Fármacos Anti-HIV/farmacologia , Descoberta de Drogas , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Indóis/farmacologia , Ácidos Fosfínicos/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cristalografia por Raios X , Cães , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Hepatócitos/química , Hepatócitos/metabolismo , Humanos , Indóis/síntese química , Indóis/química , Macaca fascicularis , Masculino , Modelos Moleculares , Estrutura Molecular , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/química , Ratos , Ratos Sprague-Dawley , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
4.
Biotechnol Prog ; 18(4): 782-95, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12153313

RESUMO

Mammalian cell-expressed therapeutic proteins are particularly vulnerable to contamination by endogenous retrovirus-like particles (RVLPs). The Viresolve NFR filter was designed to meet the critical requirement of manufacturing a safe and virus-free therapeutic by retaining RVLPs by a minimum of six log reduction value (LRV). The NFR designation refers to retrovirus removal in a normal flow format. To qualify the product, we tested two model viruses: the 78 nm diameter phi6 bacteriophage and the 80-110 nm diameter Xenotropic Murine Leukemia Virus (X-MuLV). Robust retention was demonstrated over a wide range of process parameters. Viresolve NFR filters also retain other model adventitious viruses including 70-85 nm diameter Reovirus 3 (Reo3), 70-90 nm diameter Adenovirus 2 (Ad2), and 53 nm diameter PR772 by >6 LRV. In addition to these model viruses, the filter retains >7 LRV of both the mycoplasma Acholeplasma laidlawii and the bacterium Brevundimonas diminuta. Protein passage is shown to be consistently high (95-100%) for a variety of therapeutic protein products, including monoclonal antibodies. Characterization of the filter in specific applications is made simple by availability of ultralow surface area (5 cm(2)) disks, which are shown to scale linearly to the manufacturing scale pleated-filters. Viresolve NFR filters provide consistent water permeability performance (34-37 LMH/psi) and show very little plugging for all feedstocks evaluated. The Viresolve NFR filter incorporates Retropore, a unique asymmetric polyethersulfone membrane, the surface of which has been modified to minimize protein binding.


Assuntos
Biotecnologia/métodos , Contaminação de Medicamentos/prevenção & controle , Filtração/instrumentação , Filtração/métodos , Vírus/isolamento & purificação , Animais , Bactérias/isolamento & purificação , Biotecnologia/instrumentação , Soluções Tampão , Células CHO , Cricetinae , Membranas Artificiais , Tamanho da Partícula , Permeabilidade , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Reprodutibilidade dos Testes , Soroalbumina Bovina/química , Soroalbumina Bovina/isolamento & purificação , Soluções/química , Fatores de Tempo , Vírus/classificação
5.
J Med Chem ; 54(1): 392-5, 2011 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-21142105

RESUMO

A novel series of 3-aryl-phospho-indole (API) non-nucleoside reverse transcriptase inhibitors of HIV-1 was developed. Chemical variation in the phosphorus linker led to the discovery of 3-phenyl-methyl-phosphinate-2-carboxamide 14, which possessed excellent potency against wild-type HIV-1 as well as viruses bearing K103N and Y181C single mutants in the reverse transcriptase gene. Chiral separation of the enantiomers showed that only R enantiomer retained the activity. The pharmacokinetic, solubility, and metabolic properties of 14 were assessed.


Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , Indóis/síntese química , Ácidos Fosfínicos/síntese química , Inibidores da Transcriptase Reversa/síntese química , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Cães , Farmacorresistência Viral , Transcriptase Reversa do HIV/genética , Haplorrinos , Hepatócitos/metabolismo , Humanos , Indóis/farmacocinética , Indóis/farmacologia , Modelos Moleculares , Mutação , Ácidos Fosfínicos/farmacocinética , Ácidos Fosfínicos/farmacologia , Ratos , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/farmacologia , Solubilidade , Estereoisomerismo , Relação Estrutura-Atividade
6.
Biologicals ; 36(2): 88-98, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17997110

RESUMO

Viral clearance studies for naïve and maximally cycled chromatographic resins used for cGMP recombinant protein production are reviewed for three products, comprising 10 different chromatographic steps, including affinity, ion exchange, immobilized metal ion affinity, and hydrophobic interaction modes. Thirty-two separate studies were conducted (over 90 runs in total). No consistent reductions in model virus clearance were observed with used resins. The results address the reproducibility of virus clearance studies conducted by different scientists over several years at multiple contract labs. The log reduction values (LRVs) are typically within 0.5 LRVs for new and used resin, but varied as much as 2 LRVs for resins showing no functional deterioration. This relatively large difference is not believed to reflect resin changes, but highlights the challenges encountered in modeling column clearance. Production column performance and cleaning efficacy are demonstrated for these steps by trending mock runs, impurity removal and product recovery. No deterioration in cGMP column performance is seen over the established resin lifetimes, confirming that the resin regeneration and sanitization procedures restore the resins to a suitable initial state without damage. It is proposed that for some chromatography steps, the combination of lab-scale cycling studies confirming consistent performance throughout the resin lifetime and monitoring of cGMP manufacturing preclude the need for virus clearance studies on maximally cycled resin.


Assuntos
Cromatografia de Afinidade , Resinas de Troca Iônica , Vírus/isolamento & purificação , Animais , Cromatografia por Troca Iônica , Humanos , Proteínas Recombinantes/isolamento & purificação
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