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1.
Proc Natl Acad Sci U S A ; 113(41): 11501-11506, 2016 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-27663736

RESUMO

A variable region fusion strategy was used to generate an immunosuppressive antibody based on a novel "stalk-knob" structural motif in the ultralong complementary-determining region (CDR) of a bovine antibody. The potent Kv1.3 channel inhibitory peptides Moka1-toxin and Vm24-toxin were grafted into different CDRs of the humanized antibodies BVK and Synagis (Syn) using both ß-sheet and coiled-coil linkers. Structure-activity relationship efforts led to generation of the fusion protein Syn-Vm24-CDR3L, which demonstrated excellent selectivity and potency against effector human memory T cells (subnanomolar to picomolar EC50 values). This fusion antibody also had significantly improved plasma half-life and serum stability in rodents compared with the parent Vm24 peptide. Finally, this fusion protein showed potent in vivo efficacy in the delayed type hypersensitivity in rats. These results illustrate the utility of antibody CDR fusions as a general and effective strategy to generate long-acting functional antibodies, and may lead to a selective immunosuppressive antibody for the treatment of autoimmune diseases.


Assuntos
Anticorpos Bloqueadores/farmacologia , Desenho de Fármacos , Imunossupressores/farmacologia , Canal de Potássio Kv1.3/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Células CHO , Bovinos , Regiões Determinantes de Complementaridade/química , Cricetinae , Cricetulus , Células HEK293 , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ratos , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/farmacologia
2.
J Med Chem ; 53(1): 77-105, 2010 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-19928766

RESUMO

The discovery, synthesis, and optimization of compound 1 from a high-throughput screening hit to highly potent and selective peroxisome proliferator-activated receptor delta (PPARdelta) agonists are reported. The synthesis and structure-activity relationship in this series are described in detail. On the basis of a general schematic PPAR pharmacophore model, scaffold 1 was divided into headgroup, linker, and tailgroup and successively optimized for PPAR activation using in vitro PPAR transactivation assays. A (2-methylphenoxy)acetic acid headgroup, a flexible linker, and a five-membered heteroaromatic center ring with two hydrophobic aryl substituents were required for efficient and selective PPARdelta activation. The fine-tuning of these aryl substituents led to an array of highly potent and selective compounds such as compound 38c, displaying an excellent pharmacokinetic profile in mouse. In an in vivo acute dosing model, selected members of this array were shown to induce the expression of pyruvate dehydrogenase kinase-4 (PDK4) and uncoupling protein-3 (UCP3), genes that are known to be involved in energy homeostasis and regulated by PPARdelta in skeletal muscle.


Assuntos
Oxazóis/farmacologia , PPAR delta/agonistas , Tiazóis/farmacologia , Animais , Avaliação Pré-Clínica de Medicamentos , Transferência Ressonante de Energia de Fluorescência , Ensaios de Triagem em Larga Escala , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Estrutura Molecular , Oxazóis/síntese química , Oxazóis/química , PPAR delta/genética , Estereoisomerismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/química
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