RESUMO
Small-molecule modulators of TLR8 have drawn much interests as it plays pivotal roles in the innate immune response to single-stranded RNAs (ssRNAs) derived from viruses. However, their clinical uses are limited because they can invoke an uncontrolled, global inflammatory response. The efforts described herein culminate in the fortuitous discovery of a tetrasubstituted imidazole CU-CPD107 which inhibits R848-induced TLR8 signaling. In stark contrast, CU-CPD107 shows unexpected synergistic agonist activities in the presence of ssRNA, while CU-CPD107 alone is unable to influence TLR8 signaling. CU-CPD107's unique, dichotomous behavior sheds light on a way to approach TLR agonists. CU-CPD107 offers the opportunity to avoid the undesired, global inflammation side effects that have rendered imidazoquinolines clinically irrelevant, providing an insight for the development of antiviral drugs.
Assuntos
Imidazóis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/antagonistas & inibidores , Calorimetria , Células HEK293 , Humanos , Imidazóis/síntese química , Imidazóis/química , Inflamação , Simulação de Acoplamento Molecular , Quinolinas/química , Quinolinas/farmacologia , RNA/química , RNA/farmacologia , Proteínas Recombinantes , Transdução de Sinais/imunologia , Relação Estrutura-Atividade , Receptor 8 Toll-Like/química , Receptor 8 Toll-Like/metabolismo , Difração de Raios XRESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the world. While the role of NSAIDs as cyclooxygenase (COX) inhibitors is well established, other targets may contribute to anti-inflammation. Here we report caspases as a new pharmacological target for NSAID family drugs such as ibuprofen, naproxen, and ketorolac at physiologic concentrations both in vitro and in vivo. We characterize caspase activity in both in vitro and in cell culture, and combine computational modeling and biophysical analysis to determine the mechanism of action. We observe that inhibition of caspase catalysis reduces cell death and the generation of pro-inflammatory cytokines. Further, NSAID inhibition of caspases is COX independent, representing a new anti-inflammatory mechanism. This finding expands upon existing NSAID anti-inflammatory behaviors, with implications for patient safety and next-generation drug design.
Assuntos
Anti-Inflamatórios não Esteroides/química , Inibidores de Caspase/química , Caspases/metabolismo , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Caspase/metabolismo , Inibidores de Caspase/farmacologia , Caspases/química , Caspases Iniciadoras/química , Caspases Iniciadoras/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Humanos , Ibuprofeno/química , Ibuprofeno/metabolismo , Ibuprofeno/farmacologia , Concentração Inibidora 50 , Cetorolaco/química , Cetorolaco/metabolismo , Cetorolaco/farmacologia , Naproxeno/química , Naproxeno/metabolismo , Naproxeno/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Especificidade por SubstratoRESUMO
The last two decades have seen the rise of antimicrobial peptides (AMPs) to combat emerging antibiotic resistance. Herein we report the solid-phase synthesis of short lipidated α/γ-AA hybrid peptides. This family of lipo-chimeric peptidomimetics displays potent and broad-spectrum antimicrobial activity against a range of multi-drug resistant Gram-positive and Gram-negative bacteria. These lipo-α/γ-AA hybrid peptides also demonstrate high biological specificity, with no hemolytic activity towards red blood cells. Fluorescence microscopy suggests that these lipo-α/γ-AA chimeric peptides can mimic the mode of action of AMPs and kill bacterial pathogens via membrane disintegration. As the composition of these chimeric peptides is simple, therapeutic development could be economically feasible and amenable for a variety of antimicrobial applications.
