RESUMO
The ubiquitin-specific protease 7 (USP7)-murine double minute 2 (MDM2)-p53 network plays an important role in the regulation of p53, a tumor suppressor which plays critical roles in regulating cell growth, proliferation, cell cycle progression, apoptosis and immune response. The overexpression of USP7 and MDM2 in human cancers contributes to cancer initiation and progression, and their inhibition reactivates p53 signalings and causes cell cycle arrest and apoptosis. Herein, the current state of pharmacological characterization, potential applications in cancer treatment and mechanism of action of small molecules used to target and inhibit MDM2 and USP7 proteins are highlighted, along with the outcomes in clinical and preclinical settings. Moreover, challenges and advantages of these strategies, as well as perspectives in USP7-MDM2-p53 field are analyzed in detail. The investigation and application of MDM2 and USP7 inhibitors will deepen our understanding of the function of USP7-MDM2-p53 network, and feed in the development of effective and safe cancer therapies where USP7-MDM2-p53 network is implicated.
Assuntos
Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Antineoplásicos/química , Humanos , Estrutura Molecular , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Bibliotecas de Moléculas Pequenas/química , Proteína Supressora de Tumor p53/metabolismo , Peptidase 7 Específica de Ubiquitina/metabolismoRESUMO
Bacterial infections cause a variety of life-threatening diseases, and the continuous evolution of drug-resistant bacteria poses an increasing threat to current antimicrobial regimens. Gram-positive bacteria (GPB) have a wide range of genetic capabilities that allow them to adapt to and develop resistance to practically all existing antibiotics. Oxazolidinones, a class of potent bacterial protein synthesis inhibitors with a unique mechanism of action involving inhibition of bacterial ribosomal translation, has emerged as the antibiotics of choice for the treatment of drug-resistant GPB infections. In this review, we discussed the oxazolidinone antibiotics that are currently on the market and in clinical development, as well as an updated synopsis of current advances on their analogues, with an emphasis on innovative strategies for structural optimization of linezolid, structure-activity relationship (SAR), and safety properties. We also discussed recent efforts aimed at extending the activity of oxazolidinones to gram-negative bacteria (GNB), antitumor, and coagulation factor Xa. Oxazolidinone antibiotics can accumulate in GNB by a conjugation to siderophore-mediated ß-lactamase-triggered release, making them effective against GNB.
Assuntos
Anti-Infecciosos , Oxazolidinonas , Antibacterianos/química , Oxazolidinonas/farmacologia , Oxazolidinonas/química , Linezolida/farmacologia , Relação Estrutura-Atividade , Anti-Infecciosos/farmacologia , Bactérias Gram-Negativas , Testes de Sensibilidade MicrobianaRESUMO
Global public health is facing a serious problem as a result of the rise in antibiotic resistance and the decline in the discovery of new antibiotics. In this study, two series of amphiphilic-cephalosporins were designed and synthesized, several of which showed good antibacterial activity against both Gram-positive and Gram-negative bacteria. Structure-activity relationships indicated that the length of the hydrophobic alkyl chain significantly affects the antibacterial activity against Gram-negative bacteria. The best compound 2d showed high activity against drug-susceptible Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) with MICs of 0.5 and 2-4 µg/mL, respectively. Furthermore, 2d remained active in complex mammalian body fluids and had a longer post-antibiotic effect (PAE) than vancomycin. Mechanism studies indicated that compound 2d lacks membrane-damaging properties and can target penicillin-binding proteins to disrupt bacterial cell wall structure, inhibit the metabolic activity and induce the accumulation of reactive oxygen species (ROS) in bacteria. Compound 2d showed minimal drug resistance and was nontoxic to HUVEC and HBZY-1 cells with CC50 > 128 µg/mL. These findings suggest that 2d is a promising drug candidate for treating bacterial infections.
Assuntos
Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Antibacterianos/química , Cefalosporinas/farmacologia , Bactérias Gram-Positivas , Bactérias Gram-Negativas , Monobactamas/farmacologia , Testes de Sensibilidade Microbiana , MamíferosRESUMO
The development of bacterial resistance to the majority of clinically significant antimicrobials has made it more difficult to treat bacterial infections with conventional antibiotics. As part of ongoing research on antimicrobial peptide mimetics, a series of quaternary ammonium cationic compounds with various linkers were designed and synthesized, with some demonstrating high antibacterial activity against Gram-negative and Gram-positive bacteria. The structure-activity relationship study revealed that the spatial position of substituents had a significant impact on antibacterial activity and hemolytic toxicity. The best compound, 3e, has good antibacterial activity against Staphylococcus aureus [minimum inhibitory concentration (MIC = 1 µg/mL)] and the least hemolytic toxicity [hemolytic concentration (HC50 = 905 µg/mL)], is stable in mammalian body fluids, and rarely induces bacterial resistance. The mechanism study revealed that the membrane action mode may be its potential bactericidal mechanism, and it can effectively cause the accumulation of intracellular reactive oxygen species (ROS) for killing bacteria. Importantly, 3e can effectively reduce the load of methicillin-resistant Staphylococcus aureus (MRSA) in mouse skin and has a higher in vivo bactericidal efficiency than vancomycin. These findings highlight the significance of divergent linkers in quaternary ammonium cations as antimicrobial peptide mimics and the potential of these cations to treat bacterial infections.
Assuntos
Compostos de Amônio , Staphylococcus aureus Resistente à Meticilina , Camundongos , Animais , Peptídeos Antimicrobianos , Antibacterianos/química , Testes de Sensibilidade Microbiana , Cátions/farmacologia , Compostos de Amônio/farmacologia , MamíferosRESUMO
Human ubiquitin-specific protease 7 (USP7) is a deubiquitinating enzyme that removes the ubiquitin (Ub) protein and spares substrates from degradation. Given its regulation of proteins involved in several cellular processes, abnormal expression and activity of USP7 are associated with several types of disease, including cancer. In this review, we summarize the developments in our understanding of USP7 over the past 5 years, focusing on its role in related cancers. Furthermore, we discuss clinical studies of USP7, including in vivo and pharmacological studies, as well as the development of USP7 inhibitors. A comprehensive understanding of USP7 will expand our knowledge of the structure and function of USP7-mediated signaling and shed light on drug discovery for different diseases in which USP7 is implicated.
Assuntos
Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Peptidase 7 Específica de Ubiquitina/antagonistas & inibidores , Animais , Antineoplásicos/farmacologia , Desenvolvimento de Medicamentos , Descoberta de Drogas , Humanos , Neoplasias/enzimologia , Inibidores de Proteases/farmacologia , Peptidase 7 Específica de Ubiquitina/metabolismoRESUMO
Pathogenic bacteria use an intercellular chemical communication system called quorum sensing (QS) to control the expression of cellular functions such as virulence factors, biofilm formation, toxin production, and antibiotic resistance in a manner that is highly dependent on population density. Hence, since the emergence of QS, there has been a great interest in exploiting the QS mechanism as a new drug target. Therefore, blocking the QS mechanism can be an effective strategy to control infection and solve the problem of drug resistance. So far, there is no clinically approved anti-QS drug that can disable the circuits of QS systems. This review discusses the quorum-sensing network systems and novel anti-QS inhibitors in some Gram-negative bacteria.