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1.
Bioconjug Chem ; 32(9): 2073-2082, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34415731

RESUMO

Chemically synthesized, small peptides that bind with high affinity and specificity to CD8-expressing (CD8+) tumor-infiltrating T cells, yet retain the desirable characteristics of small molecules, hold valuable potential for diagnostic molecular imaging of immune response. Here, we report the development of 18F-labeled peptides targeting human CD8α with nanomolar affinity via the strain-promoted sydnone-alkyne cycloaddition with 4-[18F]fluorophenyl sydnone. The 18F-sydnone is produced in one step, in high radiochemical yield, and the peptide labeling proceeds rapidly. A hydrophilic chemical linker results in a tracer with favorable pharmacokinetic properties and improved image contrast, as demonstrated by in vivo PET imaging studies.


Assuntos
Alcinos , Tomografia por Emissão de Pósitrons , Animais , Reação de Cicloadição , Radioisótopos de Flúor
2.
Chemistry ; 24(15): 3760-3767, 2018 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-29319889

RESUMO

The IL-17 cytokine family is associated with multiple immune and autoimmune diseases and comprises important diagnostic and therapeutic targets. This work reports the development of epitope-targeted ligands designed for differential detection of human IL-17F and its closest homologue IL-17A. Non-overlapping and unique epitopes on IL-17F and IL-17A were identified by comparative sequence analysis of the two proteins. Synthetic variants of these epitopes were utilized as targets for in situ click screens against a comprehensive library of synthetic peptide macrocycles with 5-mer variable regions. Single generation screens yielded selective binders for IL-17F and IL-17A with low cross-reactivity. Macrocyclic peptide binders against two distinct IL-17F epitopes were coupled using variable length chemical linkers to explore the physical chemistry of cooperative binding. The optimized linker length yielded a picomolar affinity binder, while retaining high selectivity. The presented method provides a rational approach towards targeting discontinuous epitopes, similar to what is naturally achieved by many B cell receptors.


Assuntos
Epitopos/química , Interleucina-17/metabolismo , Peptídeos/metabolismo , Citocinas , Humanos , Interleucina-17/imunologia , Ligantes , Ligação Proteica , Transdução de Sinais
3.
Biopolymers ; 108(2)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27539157

RESUMO

We report on peptide-based ligands matured through the protein catalyzed capture (PCC) agent method to tailor molecular binders for in vitro sensing/diagnostics and in vivo pharmacokinetics parameters. A vascular endothelial growth factor (VEGF) binding peptide and a peptide against the protective antigen (PA) protein of Bacillus anthracis discovered through phage and bacterial display panning technologies, respectively, were modified with click handles and subjected to iterative in situ click chemistry screens using synthetic peptide libraries. Each azide-alkyne cycloaddition iteration, promoted by the respective target proteins, yielded improvements in metrics for the application of interest. The anti-VEGF PCC was explored as a stable in vivo imaging probe. It exhibited excellent stability against proteases and a mean elimination in vivo half-life (T1/2 ) of 36 min. Intraperitoneal injection of the reagent results in slow clearance from the peritoneal cavity and kidney retention at extended times, while intravenous injection translates to rapid renal clearance. The ligand competed with the commercial antibody for binding to VEGF in vivo. The anti-PA ligand was developed for detection assays that perform in demanding physical environments. The matured anti-PA PCC exhibited no solution aggregation, no fragmentation when heated to 100°C, and > 81% binding activity for PA after heating at 90°C for 1 h. We discuss the potential of the PCC agent screening process for the discovery and enrichment of next generation antibody alternatives.


Assuntos
Química Click/métodos , Biblioteca de Peptídeos , Peptídeos/química , Fator A de Crescimento do Endotélio Vascular/química , Sequência de Aminoácidos , Animais , Anticorpos/administração & dosagem , Anticorpos/química , Anticorpos/metabolismo , Antígenos de Bactérias/química , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Toxinas Bacterianas/química , Toxinas Bacterianas/imunologia , Toxinas Bacterianas/metabolismo , Varredura Diferencial de Calorimetria , Catálise , Cromatografia Líquida de Alta Pressão , Dicroísmo Circular , Neoplasias do Colo/diagnóstico por imagem , Neoplasias do Colo/metabolismo , Feminino , Células HT29 , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Ligantes , Masculino , Espectrometria de Massas , Camundongos , Microssomos Hepáticos/metabolismo , Peptídeos/metabolismo , Peptídeos/farmacocinética , Ligação Proteica , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/metabolismo
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