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1.
Bioorg Med Chem ; 28(19): 115679, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32912430

RESUMO

The therapy of chronic hepatitis C virus infections has significantly improved with the development of direct-acting antivirals (DAAs), which contain NS3/4A protease, NS5A, and NS5B polymerase inhibitors. However, mutations in specific residues in these viral target genes are associated with resistance to the DAAs. Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations. As a result, the mutations influence the virological outcomes after DAA treatment. CypA inhibitors, as host-targeted agents, act on host factors to inhibit HCV replication, exhibiting a high resistance barrier and pan-genotype activities against HCV. Therefore, they can be developed into alternative, more effective anti-HCV agents. However, CypA inhibitors are natural products and analogs. Based on previous studies, bisamide derivatives were designed and synthesized to develop a novel class of CypA inhibitors. Bisamide derivative 7c is a promising compound with potent anti-HCV activity at subtoxic concentrations. Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for anti-HCV treatment.


Assuntos
Antivirais/farmacologia , Ciclofilina A/antagonistas & inibidores , Diamida/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Terapia de Alvo Molecular , Antivirais/síntese química , Antivirais/química , Linhagem Celular Tumoral , Ciclofilina A/genética , Ciclofilina A/metabolismo , Diamida/síntese química , Diamida/química , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Hepatite C Crônica/metabolismo , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície
2.
Eur J Med Chem ; 188: 112031, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31923861

RESUMO

Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 µM, but no cytotoxicity at 100 µM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a KD of 3.66 µM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinational therapy in the future.


Assuntos
Amidas/farmacologia , Antivirais/farmacologia , Ciclofilina A/antagonistas & inibidores , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Amidas/síntese química , Amidas/química , Antivirais/síntese química , Antivirais/química , Sobrevivência Celular/efeitos dos fármacos , Ciclofilina A/metabolismo , Relação Dose-Resposta a Droga , Hepacivirus/metabolismo , Hepatite C/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Células Tumorais Cultivadas
3.
J Clin Invest ; 129(4): 1684-1698, 2019 03 11.
Artigo em Inglês | MEDLINE | ID: mdl-30855276

RESUMO

Retinoic acid-related orphan receptor α (RORα) is considered a key regulator of polarization in liver macrophages that is closely related to nonalcoholic steatohepatitis (NASH) pathogenesis. However, hepatic microenvironments that support the function of RORα as a polarity regulator were largely unknown. Here, we identified maresin 1 (MaR1), a docosahexaenoic acid (DHA) metabolite with a function of specialized proresolving mediator, as an endogenous ligand of RORα. MaR1 enhanced the expression and transcriptional activity of RORα and thereby increased the M2 polarity of liver macrophages. Administration of MaR1 protected mice from high-fat diet-induced NASH in a RORα-dependent manner. Surprisingly, RORα increased the level of MaR1 through transcriptional induction of 12-lipoxygenase (12-LOX), a key enzyme in MaR1 biosynthesis. Furthermore, we demonstrated that modulation of 12-LOX activity enhanced the protective function of DHA against NASH. Together, these results suggest that the MaR1/RORα/12-LOX autoregulatory circuit could offer potential therapeutic strategies for curing NASH.


Assuntos
Araquidonato 12-Lipoxigenase/biossíntese , Ácidos Docosa-Hexaenoicos/farmacologia , Macrófagos/metabolismo , Hepatopatia Gordurosa não Alcoólica , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Animais , Araquidonato 12-Lipoxigenase/genética , Gorduras na Dieta/efeitos adversos , Gorduras na Dieta/farmacologia , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/prevenção & controle , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética
4.
Expert Opin Ther Pat ; 26(2): 229-43, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26610159

RESUMO

INTRODUCTION: A number of plant-derived agents are used in many therapeutic areas. Berberine, an important protoberberine alkaloid, is present in a number of medicinal plants that have been widely used in traditional Chinese medicine for hundreds of years. Modern research has shown that berberine and its derivatives display several pharmacological effects through various mechanisms. AREAS COVERED: This review discusses recent and mostly Chinese patents that report the synthesis of berberine, berberine derivatives and berberine salts, and methods of preparation for formulations (traditional Chinese medicine) containing herbal components rich in berberine, along with their applications. The review covers several therapeutic effects of berberine, its derivatives and pharmaceutical formulations against cancer, obesity, diabetes, inflammation, atherosclerosis, Alzheimer's disease, rheumatoid arthritis and cardiovascular diseases. In addition, the mechanisms underlying the pharmacological effects are discussed. EXPERT OPINION: Modification of the functional groups of berberine has a significant effect on the pharmacological activity. However, studies on altering the atoms and size of the berberine skeleton are rare. Thus, it may be beneficial to initiate a drug development program focused on inserting heterocyclic rings of different sizes into berberine. Furthermore, structural modification to improve the safety, efficacy and selectivity is necessary to promote the use of berberine-based drugs in clinical settings.


Assuntos
Berberina/farmacologia , Desenho de Fármacos , Medicina Tradicional Chinesa , Animais , Berberina/análogos & derivados , Berberina/química , Química Farmacêutica/métodos , Humanos , Patentes como Assunto , Plantas Medicinais/química
5.
J Med Chem ; 58(24): 9546-61, 2015 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-26613291

RESUMO

Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics.


Assuntos
Antivirais/química , Ciclofilina A/antagonistas & inibidores , Glicina/análogos & derivados , Hepacivirus/efeitos dos fármacos , Ácidos Indolacéticos/química , Animais , Antivirais/farmacologia , Antivirais/toxicidade , Linhagem Celular Tumoral , Sinergismo Farmacológico , Glicina/química , Glicina/farmacologia , Glicina/toxicidade , Hepacivirus/fisiologia , Hepatite C/tratamento farmacológico , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Terapia de Imunossupressão , Ácidos Indolacéticos/farmacologia , Ácidos Indolacéticos/toxicidade , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Moleculares , Ligação Proteica , Replicon/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacos
6.
Expert Opin Ther Pat ; 23(8): 1033-56, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23611704

RESUMO

INTRODUCTION: Topoisomerases (topos) are nuclear enzymes that resolve topological problems associated with DNA during various genetic processes. The essential role of topos in vital processes of the cell, their elevated level in solid tumors and cell death due to their inhibition make topos inhibitors as a potent class of antineoplastic agents. AREAS COVERED: This review specifically summarizes patents embracing topo I, topo I and II inhibitors. The review covers topos inhibitors which are structurally close to camptothecin (CPT), natural products such as lamellarins and synthetic trisubstituted pyridines. It largely focuses on chemical entities developed by systematic structure-activity relationship (SAR) studies of natural benzo[c]phenanthridine (nitidine) and synthetic protoberberine (coralyne) established as antineoplastic agents targeting topo(s). In addition, indenoisoquinolines and evodiamines initially discovered through COMPARE analysis and receptor-based virtual screening (VS) respectively have been discussed. EXPERT OPINION: Along with conventional techniques, computer-aided VS, molecular modeling and docking studies have been applied for drug design, discovery and development. Computer-aided tools provide a rational way to explain pharmacological activities of topos inhibitors under study. Comparative study of crystal structures of topo I/II-DNA-drug ternary complex and use of appropriate pharmacological screening methods will lead to potential anticancer drugs in the coming days.


Assuntos
Antineoplásicos/farmacologia , Inibidores da Topoisomerase I/farmacologia , Inibidores da Topoisomerase II/farmacologia , Animais , Antineoplásicos/química , Desenho Assistido por Computador , DNA Topoisomerases Tipo I/efeitos dos fármacos , DNA Topoisomerases Tipo I/metabolismo , DNA Topoisomerases Tipo II/efeitos dos fármacos , DNA Topoisomerases Tipo II/metabolismo , Desenho de Fármacos , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Patentes como Assunto , Relação Estrutura-Atividade
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