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1.
Nature ; 601(7894): 612-616, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34875675

RESUMO

Because no currently available vaccine can prevent HIV infection, pre-exposure prophylaxis (PrEP) with antiretrovirals (ARVs) is an important tool for combating the HIV pandemic1,2. Long-acting ARVs promise to build on the success of current PrEP strategies, which must be taken daily, by reducing the frequency of administration3. GS-CA1 is a small-molecule HIV capsid inhibitor with picomolar antiviral potency against a broad array of HIV strains, including variants resistant to existing ARVs, and has shown long-acting therapeutic potential in a mouse model of HIV infection4. Here we show that a single subcutaneous administration of GS-CA1 provides long-term protection against repeated rectal simian-human immunodeficiency virus (SHIV) challenges in rhesus macaques. Whereas all control animals became infected after 15 weekly challenges, a single 300 mg kg-1 dose of GS-CA1 provided per-exposure infection risk reduction of 97% for 24 weeks. Pharmacokinetic analysis showed a correlation between GS-CA1 plasma concentration and protection from SHIV challenges. GS-CA1 levels greater than twice the rhesus plasma protein-adjusted 95% effective concentration conferred 100% protection in this model. These proof-of-concept data support the development of capsid inhibitors as a novel long-acting PrEP strategy in humans.


Assuntos
Antirretrovirais , Proteínas do Capsídeo , Capsídeo , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência Símia , Animais , Antirretrovirais/farmacologia , Capsídeo/efeitos dos fármacos , Proteínas do Capsídeo/antagonistas & inibidores , Proteínas do Capsídeo/metabolismo , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Síndrome de Imunodeficiência Adquirida dos Símios/prevenção & controle , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/efeitos dos fármacos
2.
Bioorg Med Chem Lett ; 29(16): 2415-2427, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31230974

RESUMO

Direct-acting antiviral inhibitors have revolutionized the treatment of hepatitis C virus (HCV) infected patients. Herein is described the discovery of velpatasvir (VEL, GS-5816), a potent pan-genotypic HCV NS5A inhibitor that is a component of the only approved pan-genotypic single-tablet regimens (STRs) for the cure of HCV infection. VEL combined with sofosbuvir (SOF) is Epclusa®, an STR with 98% cure-rates for genotype 1-6 HCV infected patients. Addition of the pan-genotypic HCV NS3/4A protease inhibitor voxilaprevir to SOF/VEL is the STR Vosevi®, which affords 97% cure-rates for genotype 1-6 HCV patients who have previously failed another treatment regimen.


Assuntos
Antivirais/farmacologia , Carbamatos/farmacologia , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/síntese química , Antivirais/química , Carbamatos/síntese química , Carbamatos/química , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Genótipo , Hepacivirus/genética , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Compostos Macrocíclicos/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Sofosbuvir/química , Relação Estrutura-Atividade , Sulfonamidas/química , Comprimidos/química , Comprimidos/farmacologia , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
3.
Bioorg Med Chem Lett ; 29(16): 2428-2436, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31133531

RESUMO

Treatment of hepatitis C virus (HCV) infection has been historically challenging due the high viral genetic complexity wherein there are eight distinct genotypes and at least 86 viral subtypes. While HCV NS3/4A protease inhibitors are an established treatment option for genotype 1 infection, limited coverage of genotypes 2 and/or 3 combined with serum alanine transaminase (ALT) elevations for some compounds has limited the broad utility of this therapeutic class. Our discovery efforts were focused on identifying an NS3/4A protease inhibitor with pan-genotypic antiviral activity, improved coverage of resistance associated substitutions, and a decreased risk of hepatotoxicity. Towards this goal, distinct interactions with the conserved catalytic triad of the NS3/4A protease were identified that improved genotype 3 antiviral activity. We further discovered that protein adduct formation strongly correlated with clinical ALT elevation for this therapeutic class. Improving metabolic stability and decreasing protein adduct formation through structural modifications ultimately resulted in voxilaprevir. Voxilaprevir, in combination with sofosbuvir and velpatasvir, has demonstrated pan-genotypic antiviral clinical activity. Furthermore, hepatotoxicity was not observed in Phase 3 clinical trials with voxilaprevir, consistent with our design strategy. Vosevi® (sofosbuvir, velpatasvir, and voxilaprevir) is now an approved pan-genotypic treatment option for the most difficult-to-cure individuals who have previously failed direct acting antiviral therapy.


Assuntos
Antivirais/farmacologia , Carbamatos/química , Descoberta de Drogas , Hepacivirus/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Inibidores de Proteases/farmacologia , Sofosbuvir/química , Sulfonamidas/química , Sulfonamidas/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Ácidos Aminoisobutíricos , Antivirais/síntese química , Antivirais/química , Ciclopropanos , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Hepacivirus/genética , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Compostos Macrocíclicos/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Prolina/análogos & derivados , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Quinoxalinas , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
4.
ACS Med Chem Lett ; 15(4): 546-554, 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38628802

RESUMO

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.

5.
Toxicol Sci ; 186(2): 298-308, 2022 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-35134235

RESUMO

The nonclinical safety profile of GS-8873, a hepatitis B virus RNA transcript inhibitor was evaluated in rat and monkey 13-week toxicity studies with 8-week recovery phases. Vehicle or GS-8873 was dosed orally for 13 weeks at 2, 6, 20, and 60 mg/kg/day to Wistar Han rats and at 0.5, 1.5, 3, and 6 mg/kg/day to cynomolgus monkeys. In vitro and in vivo screening results from an analog discovered prior to GS-8873 informed the 13-week toxicology study designs. Neuroelectrophysiology and neurobehavioral evaluations were included at weeks 4 and 13 of the dosing and recovery phases for GS-8873. No adverse neurobehavioral effects were observed. Significant nerve conduction velocity (NCV) decreases and latency increases occurred at the high doses after 4 weeks of dosing. By week 13, dose-responsive NCV reductions and latency increases worsened across all dose groups compared with controls. Some reversal occurred 8 weeks after the last dose administered, but not to vehicle control levels. A minimal, axonal degeneration was observed in rat spinal and peripheral nerves across dose groups compared with controls. No monkey nervous system microscopic findings were observed. No-observed-adverse-effect-levels could not be determined for either species due to the neuroelectrophysiology findings and development was halted in the interest of safety. A retrospective risk assessment approach utilizing benchmark dose (BMD) modeling contributed 13-week NCV BMDL estimates (lower limits of the 95% confidence interval) in lieu of no-observed-adverse-effect-levels. The best-fitted models extrapolated NCV BMDLs for the rat caudal and monkey sural nerve at 0.3 and 0.1 mg/kg/day, respectively.


Assuntos
Antivirais , Vírus da Hepatite B , Administração Oral , Animais , Antivirais/farmacologia , Antivirais/toxicidade , Haplorrinos , Vírus da Hepatite B/efeitos dos fármacos , Ratos , Ratos Wistar , Estudos Retrospectivos
6.
J Am Chem Soc ; 132(1): 275-80, 2010 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-19968285

RESUMO

This Article describes an enantioselective synthesis of cephalostatin 1. Key steps of this synthesis are a unique methyl group selective allylic oxidation, directed C-H hydroxylation of a sterol at C12, Au(I)-catalyzed 5-endo-dig cyclization, and a kinetic spiroketalization.


Assuntos
Fenazinas/química , Fenazinas/síntese química , Compostos de Espiro/química , Compostos de Espiro/síntese química , Esteroides/química , Esteroides/síntese química , Antineoplásicos/síntese química , Antineoplásicos/química , Estereoisomerismo , Especificidade por Substrato
7.
PLoS One ; 10(4): e0122844, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25856426

RESUMO

Ledipasvir, a direct acting antiviral agent (DAA) targeting the Hepatitis C Virus NS5A protein, exhibits picomolar activity in replicon cells. While its mechanism of action is unclear, mutations that confer resistance to ledipasvir in HCV replicon cells are located in NS5A, suggesting that NS5A is the direct target of ledipasvir. To date co-precipitation and cross-linking experiments in replicon or NS5A transfected cells have not conclusively shown a direct, specific interaction between NS5A and ledipasvir. Using recombinant, full length NS5A, we show that ledipasvir binds directly, with high affinity and specificity, to NS5A. Ledipasvir binding to recombinant NS5A is saturable with a dissociation constant in the low nanomolar range. A mutant form of NS5A (Y93H) that confers resistance to ledipasvir shows diminished binding to ledipasvir. The current study shows that ledipasvir inhibits NS5A through direct binding and that resistance to ledipasvir is the result of a reduction in binding affinity to NS5A mutants.


Assuntos
Antivirais/farmacologia , Benzimidazóis/farmacologia , Farmacorresistência Viral/genética , Fluorenos/farmacologia , Hepacivirus/efeitos dos fármacos , Mutação , Proteínas não Estruturais Virais/genética , Sequência de Aminoácidos , Antivirais/química , Benzimidazóis/química , Linhagem Celular Tumoral , Fluorenos/química , Hepacivirus/genética , Hepacivirus/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/patologia , Hepatócitos/virologia , Humanos , Cinética , Dados de Sequência Molecular , Ligação Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Replicon , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Replicação Viral
8.
J Med Chem ; 57(5): 2033-46, 2014 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-24320933

RESUMO

A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered. Optimization of antiviral potency and pharmacokinetics led to the identification of 39 (ledipasvir, GS-5885). Compound 39 (GT1a replicon EC50 = 31 pM) has an extended plasma half-life of 37-45 h in healthy volunteers and produces a rapid >3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients. 39 has been shown to be safe and efficacious, with SVR12 rates up to 100% when used in combination with direct-acting antivirals having complementary mechanisms.


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C/tratamento farmacológico , Proteínas não Estruturais Virais/antagonistas & inibidores , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Sequência de Bases , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Primers do DNA , Método Duplo-Cego , Fluorenos/farmacocinética , Fluorenos/farmacologia , Meia-Vida , Humanos , Macaca fascicularis , Masculino , Placebos , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
10.
Proc Natl Acad Sci U S A ; 100(25): 14846-51, 2003 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-14657396

RESUMO

Mucin-type O-linked glycoproteins are involved in a variety of biological interactions in higher eukaryotes. The biosynthesis of these glycoproteins is initiated by a family of polypeptide N-acetyl-alpha-galactosaminyltransferases (ppGalNAcTs) that modify proteins in the secretory pathway. The lack of a defined consensus sequence for the ppGalNAcTs makes the prediction of mucin-type O-linked glycosylation difficult based on primary sequence alone. Herein we present a method for labeling mucin-type O-linked glycoproteins with a unique chemical tag, the azide, which permits their selective covalent modification from complex cell lysates. From a panel of synthetic derivatives, we identified an azido GalNAc analog (N-azidoacetylgalactosamine, GalNAz) that is metabolized by numerous cell types and installed on mucin-type O-linked glycoproteins by the ppGalNAcTs. The azide serves as a bioorthogonal chemical handle for selective modification with biochemical or biophysical probes using the Staudinger ligation. The approach was validated by labeling a recombinant glycoprotein that is known to possess O-linked glycans with GalNAz. In addition, GalNAz efficiently labeled mucin-type O-linked glycoproteins expressed at endogenous levels. The ability to label mucin-type O-linked glycoproteins with chemical tags should facilitate their identification by proteomic strategies.


Assuntos
Mucinas/química , Animais , Western Blotting , Células CHO , Células COS , Cricetinae , Relação Dose-Resposta a Droga , Citometria de Fluxo , Glicoproteínas/química , Glicosilação , Células HeLa , Humanos , Células Jurkat , Lectinas/química , Camundongos , Modelos Biológicos , Modelos Químicos , Monossacarídeos/química , Células NIH 3T3 , Proteoma , Proteínas Recombinantes/química
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