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1.
Angew Chem Int Ed Engl ; 60(15): 8268-8275, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33448563

RESUMO

The two gut hormones GLP-1 and PYY3-36 , which are both secreted from the L-cells upon food stimuli, have a stronger inhibitory effect on food intake when they are combined, compared to their individual effects as single agonists. Although they are not homologous and share no sequence similarity, we show that a GLP-1 analogue can be designed to exhibit potent activity on both the Y2 and GLP-1 receptors. Dual acting hybrid analogues were realized by designing truncated and potent Y2 receptor PYY analogues, followed by integrating the critical residues into GLP-1. In this study, we show that one of these dual acting agonists acutely reduces food intake significantly more than the respective mono-agonist counterparts.


Assuntos
Desenho de Fármacos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Fragmentos de Peptídeos/farmacologia , Peptídeo YY/farmacologia , Receptores dos Hormônios Gastrointestinais/agonistas , Cristalografia por Raios X , Peptídeo 1 Semelhante ao Glucagon/síntese química , Peptídeo 1 Semelhante ao Glucagon/química , Humanos , Modelos Moleculares , Fragmentos de Peptídeos/síntese química , Fragmentos de Peptídeos/química , Peptídeo YY/síntese química , Peptídeo YY/química
2.
Chembiochem ; 21(23): 3338-3348, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-32667131

RESUMO

The controlled self-assembly of peptide- and protein-based pharmaceuticals is of central importance for their mode of action and tuning of their properties. Peptide YY3-36 (PYY3-36 ) is a 36-residue peptide hormone that reduces food intake when peripherally administered. Herein, we describe the synthesis of a PYY3-36 analogue functionalized with a metal-ion-binding 2,2'-bipyridine ligand that enables self-assembly through metal complexation. Upon addition of CuII , the bipyridine-modified PYY3-36 peptide binds stoichiometric quantities of metal ions in solution and contributes to the organization of higher-order assemblies. In this study, we aimed to explore the size effect of the self-assembly in vivo by using non-invasive quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. For this purpose, bipyridine-modified PYY3-36 was radiolabeled with a chelator holding 111 InIII , followed by the addition of CuII to the bipyridine ligand. SPECT/CT imaging and biodistribution studies showed fast renal clearance and accumulation in the kidney cortex. The radiolabeled bipyridyl-PYY3-36 conjugates with and without CuII presented a slightly slower excretion 1 h post injection compared to the unmodified-PYY3-36 , thus demonstrating that higher self-assemblies of the peptide might have an effect on the pharmacokinetics.


Assuntos
Cobre/farmacocinética , Peptídeo YY/farmacocinética , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , 2,2'-Dipiridil/química , 2,2'-Dipiridil/farmacocinética , Animais , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/farmacocinética , Cobre/química , Feminino , Córtex Renal/química , Córtex Renal/metabolismo , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Peptídeo YY/síntese química , Peptídeo YY/química , Eliminação Renal , Distribuição Tecidual
3.
Chembiochem ; 11(3): 366-74, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20049760

RESUMO

The increasing prevalence of obesity worldwide calls for safe and highly efficacious satiety drugs. PYY3-36 has been implicated in food intake regulation, and novel peptide analogues with high Y2 receptor-subtype selectivity and potency have potential as drugs for the treatment of obesity. It has been hypothesized that PYY3-36 associates with the plasma membrane prior to receptor activation such that the amphipathic alpha-helix of PYY3-36 possibly guides the C-terminal pentapeptide into the correct conformation for receptor activation. Ala-scans are used routinely to study the effect of individual amino acids in a given peptide sequence. Here we report the glyco-scan of the peptide hormone PYY3-36, in which hydroxyl side-chain functionalities were glycosylated; in addition new glycosylation sites were introduced. An array of novel PYY3-36 analogues with a glycan positioned in the water-membrane interface or in the N terminal were screened for Y-receptor affinity and selectivity as well as metabolic stability. Interestingly, in contrast to the Y1 and Y4 receptors, the Y2 receptor readily accommodated glycosylations. Especially glycosylations in the alpha-helical region of PYY3-36 were favorable both in terms of Y-receptor selectivity and endopeptidase resistance. We thus report several PYY3-36 analogues with enhanced Y-receptor selectivity. Our results can be used in the design of novel PYY analogues for the treatment of obesity. The glyco-scan concept, as systematically demonstrated here, has the potential for a wider applicability.


Assuntos
Peptídeo YY/metabolismo , Animais , Dicroísmo Circular , Glicosilação , Humanos , Camundongos , Obesidade/tratamento farmacológico , Fragmentos de Peptídeos , Peptídeo YY/síntese química , Peptídeo YY/química , Estrutura Secundária de Proteína , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-Atividade
5.
Peptides ; 29(1): 112-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18082288

RESUMO

Peptide YY (3-36) [PYY(3-36)] inhibits feeding in rodents, nonhuman primates and humans, yet the neural circuits underlying this action remain to be determined. Here we assessed whether PYY(3-36) inhibits feeding by activating neurons in forebrain and hindbrain sites containing Y2 receptors and linked to control of food intake, or in hindbrain sites immediately downstream of vagal afferent neurons. Rats received an anorexigenic dose of PYY(3-36), and the number of neurons expressing Fos, an indicator of neuronal activation, was determined in anterior hypothalamus (AH), arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), lateral hypothalamus (LH), ventromedial hypothalamus (VMH), central nucleus of the amygdala (CeA), area postrema (AP), and caudal medial nucleus tractus solitarius (cmNTS), commissural NTS (cNTS), and gelatinosus NTS (gNTS). Expression of tyrosine hydroxylase (TH), an indicator of catecholamine synthesis, was also measured in the cmNTS. PYY(3-36) increased Fos in ARC, cmNTS, gNTS and AP. Approximately 10% of Fos+ neurons in the cmNTS were TH+. These results suggest that PYY(3-36) inhibits feeding through direct activation of ARC neurons, and direct and/or indirect activation via vagal afferent nerves of cmNTS, gNTS and AP, including some catecholaminergic neurons in the cmNTS.


Assuntos
Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Catecolaminas/metabolismo , Neurônios/efeitos dos fármacos , Peptídeo YY/administração & dosagem , Proteínas Proto-Oncogênicas c-fos/biossíntese , Núcleo Solitário/efeitos dos fármacos , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Imuno-Histoquímica , Infusões Intravenosas , Masculino , Neurônios/metabolismo , Fragmentos de Peptídeos , Peptídeo YY/síntese química , Peptídeo YY/isolamento & purificação , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/metabolismo , Tirosina 3-Mono-Oxigenase/biossíntese , Tirosina 3-Mono-Oxigenase/efeitos dos fármacos
6.
Bioorg Med Chem Lett ; 17(7): 1916-9, 2007 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-17292607

RESUMO

Activation of the NPY2 receptor to reduce appetite while avoiding activation of the NPY1 and NPY5 receptors that stimulate feeding provides a pharmaceutical approach to modulate food intake. The naturally occurring peptide and development candidate PYY(3-36) is a non-selective NPY1, NPY2, and NPY5 agonist of limited in vivo duration of action. N-terminal modification with 20 kDa PEG of a selective NPY2 receptor agonist peptide results in a long-acting agent that outperforms PYY(3-36) in reducing food intake in mice. The results suggest that PEGylated, selective NPY2 peptide agonists offer a significantly improved therapeutic benefit over PYY(3-36) for obesity management.


Assuntos
Química Farmacêutica/métodos , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Peptídeo YY/síntese química , Peptídeo YY/farmacologia , Polietilenoglicóis/química , Receptores de Neuropeptídeo Y/química , Animais , Relação Dose-Resposta a Droga , Desenho de Fármacos , Humanos , Cinética , Camundongos , Conformação Molecular , Fragmentos de Peptídeos , Peptídeos/química , Ligação Proteica
7.
J Med Chem ; 43(18): 3420-7, 2000 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-10978189

RESUMO

Peptide YY (PYY) is a gut hormone that inhibits secretion and promotes absorption and growth in the intestinal epithelium. We have performed structure-activity studies with the active site, N-alpha-Ac-PYY(22-36)-NH(2), for interaction with intestinal PYY receptors. Investigation of aromatic substitutions at position 27 resulted in analogues that exhibited potent in vitro antisecretory potencies with N-alpha-Ac-[Trp(27)]PYY(22-36)-NH(2) exhibiting even greater potency than intact PYY. In vivo studies in dogs revealed that this analogue also promoted intestinal absorption of water and electrolytes during continuous intravenous and intraluminal infusion. Investigations carried out to identify features that would enhance stability revealed that incorporation of Trp(30) increased affinity for PYY receptors. A "CH(2)-NH" scan revealed that incorporation of reduced bonds at position 28-29 or 35-36 imparted greater receptor affinity. In general, disubstituted analogues designed based on the results of single substitutions exhibited good receptor affinity with N-alpha-Ac-[Trp(27),CH(2)-NH(35-36)]PYY(22-36)-NH(2) having the greatest affinity (IC(50) = 0.28 nM). Conservative multiple substitutions with Nle-->Leu and Nva-->Val also imparted good affinity. An analogue designed to encompass most of the favored substitutions, N-alpha-Ac-[Nle(24,28),Trp(30),Nva(31), CH(2)-NH(35-36)]PYY(22-36)-NH(2), exhibited a proabsorptive effect in dogs comparable to, but longer lasting than, that of intact hormone. Selected analogues also exhibited good antisecretory potencies in rats with N-alpha-Ac-[Trp(30)]PYY(22-36)-NH(2) being even more potent than PYY. However, the potencies did not correlate well with the PYY receptor affinity or the proabsorptive potencies in dogs. These differences could be due to species effects and/or the involvement of multiple receptors and neuronal elements in controlling the in vivo activity of PYY compounds. PYY(22-36) analogues exhibited good affinity for neuronal Y2 receptors but poor affinity for Y1 receptors. Also, crucial analogues in this series hardly bound to Y4 and Y5 receptors. In summary, we have developed PYY(22-36) analogues which, via interacting with intestinal PYY receptors, promoted potent and long-lasting proabsorptive and antisecretory effects in in vivo models. These compounds or analogues based on them may have useful clinical application in treating malabsorptive disorders observed under a variety of conditions.


Assuntos
Intestinos/efeitos dos fármacos , Fragmentos de Peptídeos/síntese química , Peptídeo YY/síntese química , Animais , Linhagem Celular , Colo/efeitos dos fármacos , Colo/metabolismo , Cães , Íleo/efeitos dos fármacos , Íleo/metabolismo , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Peptídeo YY/química , Peptídeo YY/farmacologia , Ratos , Receptores de Neuropeptídeo Y/metabolismo , Relação Estrutura-Atividade
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