RESUMO
Oral antiretroviral agents provide life-saving treatments for millions of people living with HIV, and can prevent new infections via pre-exposure prophylaxis1-5. However, some people living with HIV who are heavily treatment-experienced have limited or no treatment options, owing to multidrug resistance6. In addition, suboptimal adherence to oral daily regimens can negatively affect the outcome of treatment-which contributes to virologic failure, resistance generation and viral transmission-as well as of pre-exposure prophylaxis, leading to new infections1,2,4,7-9. Long-acting agents from new antiretroviral classes can provide much-needed treatment options for people living with HIV who are heavily treatment-experienced, and additionally can improve adherence10. Here we describe GS-6207, a small molecule that disrupts the functions of HIV capsid protein and is amenable to long-acting therapy owing to its high potency, low in vivo systemic clearance and slow release kinetics from the subcutaneous injection site. Drawing on X-ray crystallographic information, we designed GS-6207 to bind tightly at a conserved interface between capsid protein monomers, where it interferes with capsid-protein-mediated interactions between proteins that are essential for multiple phases of the viral replication cycle. GS-6207 exhibits antiviral activity at picomolar concentrations against all subtypes of HIV-1 that we tested, and shows high synergy and no cross-resistance with approved antiretroviral drugs. In phase-1 clinical studies, monotherapy with a single subcutaneous dose of GS-6207 (450 mg) resulted in a mean log10-transformed reduction of plasma viral load of 2.2 after 9 days, and showed sustained plasma exposure at antivirally active concentrations for more than 6 months. These results provide clinical validation for therapies that target the functions of HIV capsid protein, and demonstrate the potential of GS-6207 as a long-acting agent to treat or prevent infection with HIV.
Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Proteínas do Capsídeo/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Adolescente , Adulto , Fármacos Anti-HIV/química , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Linhagem Celular , Células Cultivadas , Farmacorresistência Viral/genética , Feminino , HIV-1/crescimento & desenvolvimento , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Moleculares , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
Chronic hepatitis B (CHB) virus infection afflicts hundreds of millions of people and causes nearly one million deaths annually. The high levels of circulating viral surface antigen (HBsAg) that characterize CHB may lead to T-cell exhaustion, resulting in an impaired antiviral immune response in the host. Agents that suppress HBsAg could help invigorate immunity toward infected hepatocytes and facilitate a functional cure. A series of dihydropyridoisoquinolizinone (DHQ) inhibitors of human poly(A) polymerases PAPD5/7 were reported to suppress HBsAg in vitro. An example from this class, RG7834, briefly entered the clinic. We set out to identify a potent, orally bioavailable, and safe PAPD5/7 inhibitor as a potential component of a functional cure regimen. Our efforts led to the identification of a dihydropyridophthalazinone (DPP) core with improved pharmacokinetic properties. A conformational restriction strategy and optimization of core substitution led to GS-8873, which was projected to provide deep HBsAg suppression with once-daily dosing.
RESUMO
Introduction: Cigar stacking fermentation is a key step in tobacco aroma enhancement and miscellaneous gas reduction, which both have a great influence on increasing cigar flavor and improving industrial availability. Methods: To analyze the effect of cigar tobacco leaf (CTLs) microbial community on volatiles flavor compounds (VFCs), this study used multi-omics technology to reveal the changes in microbial community structure and VFCs of different cigar varieties during stacking fermentation, in addition to exploring the interaction mechanism of microbiome and VFCs. Results: The results showed that the dominant microbial compositions of different CTL varieties during stacking fermentation were similar, which included Staphylococcus, Corynebacterium 1, Aerococcus, and Aspergillus. These dominant microbes mainly affected the microbial community structure and characteristic microorganisms of CTLs through microbial interactions, thereby influencing the transformation of VFCs. Characteristic microorganisms of different CTLs varieties such as Trichothecium, Trichosporon, Thioalkalicoccus and Jeotgalicoccus, were found to positively correlate with characteristic VFCs like megastigmatrienone 4, pyrazine, tetramethyl-, geranyl acetone, and 2-undecanone, 6,10-dimethyl-, respectively. This in turn affected the aroma and sensory quality of the CTLs. Discussion: This study provides theoretical support for the analysis of the mechanism of microorganisms on VFCs and aroma, and development of microbial agents during cigar stacking fermentation.
RESUMO
A potent and novel class of phosphinic acid derived product-like inhibitors of the HCV NS3/4A protease was discovered previously. Modification of the phosphinic acid and quinoline heterocycle led to GS-9256 with potent cell-based activity and favorable pharmacokinetic parameters. Based on these attributes, GS-9256 was advanced to human clinical trial as a treatment for chronic infection with genotype 1 HCV.
Assuntos
Proteínas de Transporte/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Peptídeos Cíclicos/química , Ácidos Fosfínicos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Cães , Inibidores Enzimáticos/síntese química , Hepacivirus/enzimologia , Humanos , Concentração Inibidora 50 , Peptídeos e Proteínas de Sinalização Intracelular , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Ácidos Fosfínicos/síntese química , Ácidos Fosfínicos/farmacologia , SuínosRESUMO
The discovery of GS-9451 is reported. Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats, dogs and monkeys.
Assuntos
Antivirais/síntese química , Ácidos Carboxílicos/síntese química , Hepacivirus/efeitos dos fármacos , Quinolinas/síntese química , Inibidores de Serina Proteinase/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/farmacocinética , Antivirais/farmacologia , Disponibilidade Biológica , Células CACO-2 , Ácidos Carboxílicos/farmacocinética , Ácidos Carboxílicos/farmacologia , Cristalografia por Raios X , Cães , Hepacivirus/química , Hepacivirus/enzimologia , Hepatite C/tratamento farmacológico , Hepatite C/virologia , Humanos , Macaca fascicularis , Modelos Moleculares , Quinolinas/farmacocinética , Quinolinas/farmacologia , Ratos , Inibidores de Serina Proteinase/farmacocinética , Inibidores de Serina Proteinase/farmacologia , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
Metabolic activity of the microbial community greatly affects the quality of cigar tobacco leaves (CTLs). To improve the quality of CTLs, two extrinsic microbes (Acinetobacter sp. 1H8 and Acinetobacter indicus 3B2) were inoculated into CTLs. The quality of CTLs were significantly improved after fermentation. The content of solanone, 6-methyl-5-hepten-2-one, benzeneacetic acid, ethyl ester, cyclohexanone, octanal, acetophenone, and 3,5,5-trimethyl-2-cyclohexen-1-one were significantly increased after inoculated Acinetobacter sp. 1H8. The inoculation of Acinetobacter sp. 1H8 enhanced the normal evolutionary trend of bacterial community. The content of trimethyl-pyrazine, 2,6-dimethyl-pyrazine, and megastigmatrienone were significantly increased after inoculated Acinetobacter indicus 3B2. The inoculation of Acinetobacter indicus 3B2 completely changed the original bacterial community. Network analysis revealed that Acinetobacter was negatively correlated with Aquabacterium, positively correlated with Bacillus, and had significant correlations with many volatile flavor compounds. This work may be helpful for improving fermentation product quality by regulating microbial community, and gain insight into the microbial ecosystem.
RESUMO
Guest molecules of diethyl ether or methanol are reversibly encapsulated in cavities formed by the 3-dimensional supramolecular framework of heteropolynuclear, luminescent [Eu2Zn4L4(OAc)6(NO3)2(OH)2].2Et2O.
RESUMO
The exploration of novel inhibitors of the HCV NS4B protein that are based on a 2-oxadiazoloquinoline scaffold is described. Optimization to incorporate activity across genotypes led to a potent new series with broad activity, of which inhibitor 1 displayed the following EC50 values: 1a, 0.08 nM; 1b, 0.10 nM; 2a, 3 nM; 2b, 0.6 nM, 3a, 3.7 nM; 4a, 0.9 nM; 6a, 3.1 nM.
Assuntos
Genótipo , Hepacivirus/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , Hepacivirus/genética , Espectroscopia de Ressonância Magnética , Espectrometria de MassasRESUMO
Catalytic signal enhancement using an organometallic reaction is demonstrated. The reactivity of a Heck cross-coupling reaction that creates a fluorophore is modulated by the addition of a polyazacyclam inhibitor. The inhibitor will complex with Cu(II), which restores the activity of the Pd(II). The addition of Cu(II) therefore leads to the generation of fluorescence, thereby creating a very sensitive assay for Cu(II). The rate of the Heck reaction is followed by monitoring emission as a function of time. The rate is proportional to the Cu(II) concentration and correlates to the affinity of the inhibitor to various metals. This strategy represents a general technique that can be exploited with other catalytic organometallic reactions.