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1.
J Am Chem Soc ; 145(19): 10445-10450, 2023 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-37155687

RESUMO

mRNA display of macrocyclic peptides has proven itself to be a powerful technique to discover high-affinity ligands for a protein target. However, only a limited number of cyclization chemistries are known to be compatible with mRNA display. Tyrosinase is a copper-dependent oxidase that oxidizes tyrosine phenol to an electrophilic o-quinone, which is readily attacked by cysteine thiol. Here we show that peptides containing tyrosine and cysteine are rapidly cyclized upon tyrosinase treatment. Characterization of the cyclization reveals it to be widely applicable to multiple macrocycle sizes and scaffolds. We combine tyrosinase-mediated cyclization with mRNA display to discover new macrocyclic ligands targeting melanoma-associated antigen A4 (MAGE-A4). These macrocycles potently inhibit the MAGE-A4 binding axis with nanomolar IC50 values. Importantly, macrocyclic ligands show clear advantage over noncyclized analogues with ∼40-fold or greater decrease in IC50 values.


Assuntos
Cisteína , Monofenol Mono-Oxigenase , Monofenol Mono-Oxigenase/metabolismo , Cisteína/metabolismo , RNA Mensageiro/metabolismo , Ligantes , Peptídeos/química , Tirosina/metabolismo , Catálise , Ciclização
3.
Bipolar Disord ; 17(4): 424-37, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25495748

RESUMO

OBJECTIVES: We conducted a randomized, controlled trial comparing the efficacy of an Integrated Risk Reduction Intervention (IRRI) to a control condition with the objective of improving mood stability and psychosocial functioning by reducing cardiometabolic risk factors in overweight/obese patients with bipolar I disorder. METHODS: A total of 122 patients were recruited from our outpatient services and randomly allocated to IRRI (n = 61) or psychiatric care with medical monitoring (n = 61). Individuals allocated to IRRI received psychiatric treatment and assessment, medical monitoring by a nurse, and a healthy lifestyle program from a lifestyle coach. Those allocated to the control condition received psychiatric treatment and assessment and referral, if indicated, for medical problems. A mixed-effects model was used to examine the impact of the interventions on body mass index (BMI). Exploratory moderator analyses were used to characterize those individuals likely to benefit from each treatment approach. RESULTS: Analyses were conducted on data for the IRRI (n = 58) and control (n = 56) participants with ≥ 1 study visit. IRRI was associated with a significantly greater rate of decrease in BMI (d = -0.51, 95% confidence interval: -0.91 to -0.14). Three variables (C-reactive protein, total cholesterol, and instability of total sleep time) contributed to a combined moderator of faster decrease in BMI with IRRI treatment. CONCLUSIONS: Overweight/obese patients with bipolar disorder can make modest improvements in BMI, even when taking medications with known potential for weight gain. Our finding that a combination of three baseline variables provides a profile of patients likely to benefit from IRRI will need to be tested further to evaluate its utility in clinical practice.


Assuntos
Transtorno Bipolar/tratamento farmacológico , Índice de Massa Corporal , Obesidade/induzido quimicamente , Obesidade/tratamento farmacológico , Sobrepeso/induzido quimicamente , Sobrepeso/psicologia , Sobrepeso/terapia , Comportamento de Redução do Risco , Adulto , Afeto/efeitos dos fármacos , Transtorno Bipolar/psicologia , Prestação Integrada de Cuidados de Saúde , Feminino , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Obesidade/psicologia , Valores de Referência , Ajustamento Social
4.
J Med Chem ; 65(10): 7231-7245, 2022 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-35522528

RESUMO

MAGE proteins are cancer testis antigens (CTAs) that are characterized by highly conserved MAGE homology domains (MHDs) and are increasingly being found to play pivotal roles in promoting aggressive cancer types. MAGE-A4, in particular, increases DNA damage tolerance and chemoresistance in a variety of cancers by stabilizing the E3-ligase RAD18 and promoting trans-lesion synthesis (TLS). Inhibition of the MAGE-A4:RAD18 axis could sensitize cancer cells to chemotherapeutics like platinating agents. We use an mRNA display of thioether cyclized peptides to identify a series of potent and highly selective macrocyclic inhibitors of the MAGE-A4:RAD18 interaction. Co-crystal structure indicates that these inhibitors bind in a pocket that is conserved across MHDs but take advantage of A4-specific residues to achieve high isoform selectivity. Cumulatively, our data represent the first reported inhibitor of the MAGE-A4:RAD18 interaction and establish biochemical tools and structural insights for the future development of MAGE-A4-targeted cellular probes.


Assuntos
Antígenos de Neoplasias , Proteínas de Neoplasias , Neoplasias , Antígenos de Neoplasias/química , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Relação Estrutura-Atividade , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
5.
Medicines (Basel) ; 5(2)2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29561753

RESUMO

Background: The woody shrub Trichostema lanatum Benth. (Lamiaceae) is native to Southern California and was reportedly used by the Chumash people as a disinfectant and for the treatment of rheumatism. Based on its traditional uses, this study investigated the antibacterial and immunomodulatory properties of extracts from T. lanatum.Methods: A methanolic extract of the leaves and stems of T. lanatum was tested for immunomodulatory activity by measuring the proliferation of murine macrophage cell cultures and the production of the pro-inflammatory cytokine TNF-α by the cells after treatment with T. lanatum. Antibacterial activity of the extract against a panel of six Gram-positive bacteria and two Gram-negative bacteria was evaluated using a disc-diffusion assay. Results: The T. lanatum extract inhibited the growth of Gram-positive bacteria, but not Gram-negative bacteria. Treatment of activated macrophage cell cultures with T. lanatum extract resulted in decreased proliferation of the activated macrophages and a decrease in the production of TNF-α. Conclusions: These results provide the first pharmacological support for the traditional use of T. lanatum by the Chumash people of Southern California as a disinfectant and treatment for rheumatism.

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