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1.
Acta Pharmacol Sin ; 44(6): 1227-1237, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-36482086

RESUMO

Parathyroid hormone (PTH) and PTH-related peptide (PTHrP) are two endogenous hormones recognized by PTH receptor-1 (PTH1R), a member of class B G protein- coupled receptors (GPCRs). Both PTH and PTHrP analogs including teriparatide and abaloparatide are approved drugs for osteoporosis, but they exhibit distinct pharmacology. Here we report two cryo-EM structures of human PTH1R bound to PTH and PTHrP in the G protein-bound state at resolutions of 2.62 Å and 3.25 Å, respectively. Detailed analysis of these structures uncovers both common and unique features for the agonism of PTH and PTHrP. Molecular dynamics (MD) simulation together with site-directed mutagenesis studies reveal the molecular basis of endogenous hormones recognition specificity and selectivity to PTH1R. These results provide a rational template for the clinical use of PTH and PTHrP analogs as an anabolic therapy for osteoporosis and other disorders.


Assuntos
Osteoporose , Proteína Relacionada ao Hormônio Paratireóideo , Humanos , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Sequência de Aminoácidos , Hormônio Paratireóideo/química , Hormônio Paratireóideo/metabolismo , Receptores Acoplados a Proteínas G , Osteoporose/tratamento farmacológico
2.
Acta Pharmacol Sin ; 44(2): 421-433, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35953646

RESUMO

The paradigm of one drug against multiple targets, known as unimolecular polypharmacology, offers the potential to improve efficacy while overcoming some adverse events associated with the treatment. This approach is best exemplified by targeting two or three class B1 G protein-coupled receptors, namely, glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR) and glucose-dependent insulinotropic polypeptide receptor for treatment of type 2 diabetes and obesity. Some of the dual and triple agonists have already shown initial successes in clinical trials, although the molecular mechanisms underlying their multiplexed pharmacology remain elusive. In this study we employed structure-based site-directed mutagenesis together with pharmacological assays to compare agonist efficacy across two key signaling pathways, cAMP accumulation and ERK1/2 phosphorylation (pERK1/2). Three dual agonists (peptide 15, MEDI0382 and SAR425899) and one triple agonist (peptide 20) were evaluated at GLP-1R and GCGR, relative to the native peptidic ligands (GLP-1 and glucagon). Our results reveal the existence of residue networks crucial for unimolecular agonist-mediated receptor activation and their distinct signaling patterns, which might be useful to the rational design of biased drug leads.


Assuntos
Diabetes Mellitus Tipo 2 , Peptídeo 1 Semelhante ao Glucagon , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/genética , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Mutagênese Sítio-Dirigida , Peptídeos/química , Receptores de Glucagon/genética , Receptores de Glucagon/agonistas , Receptores de Glucagon/metabolismo , Transdução de Sinais , Fatores de Transcrição
3.
Acta Pharmacol Sin ; 41(10): 1328-1336, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32235863

RESUMO

Relaxin/insulin-like family peptide receptor 4 (RXFP4) is a class A G protein-coupled receptor (GPCR), and insulin-like peptide 5 (INSL5) is its endogenous ligand. Although the precise physiological role of INSL5/RXFP4 remains elusive, a number of studies have suggested it to be a potential therapeutic target for obesity and other metabolic disorders. Since selective agonists of RXFP4 are scarcely available and peptidic analogs of INSL5 are hard to make, we conducted a high-throughput screening campaign against 52,000 synthetic and natural compounds targeting RXFP4. Of the 109 initial hits discovered, only 3 compounds were confirmed in secondary screening, with JK0621-D008 displaying the best agonism at human RXFP4. Its S-configuration stereoisomer (JK1) was subsequently isolated and validated by a series of bioassays, demonstrating a consistent agonistic effect in cells overexpressing RXFP4. This scaffold may provide a valuable tool to further explore the biological functions of RXFP4.


Assuntos
Receptores Acoplados a Proteínas G/agonistas , Receptores de Peptídeos/agonistas , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Células CHO , Cricetulus , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Bibliotecas de Moléculas Pequenas/toxicidade
4.
Nanotechnology ; 22(8): 085707, 2011 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-21242632

RESUMO

MnFe(2)O(4) nanocrystals (NCs) coated with three different surfactants (oleic acid, oleylamine or 1,2-hexadecanediol) and their mixtures, with sizes in range 6-12 nm, were synthesized by high-temperature decomposition of organometallic precursors. The effects of morphology and surface chemistry of MnFe(2)O(4) NCs on the magnetic properties were systematically investigated by comparing their saturation magnetization values and their capability to improve the negative contrast for magnetic resonance imaging (MRI) after converting the hydrophobic NCs to hydrophilic ones by a ligand exchange protocol. An important finding is that the magnetization values and proton relaxivity rates of MnFe(2)O(4) NCs are strongly dependent on the size and surface state of the particles that covalently bonded with different hydrophobic ligands before ligand exchange. In particular, monodisperse cubic MnFe(2)O(4) NCs could be obtained when oleylamine and 1,2-hexadecanediol were used as mixed stabilizers, and showed excellent morphology and magnetic properties. Furthermore, the low cytotoxicity and good cell uptake MR imaging of the dopamine capped MnFe(2)O(4) NCs make them promising candidates for use as bio-imaging probes.


Assuntos
Meios de Contraste/química , Compostos Férricos/química , Imageamento por Ressonância Magnética/métodos , Compostos de Manganês/química , Nanopartículas/química , Tensoativos/química , Aminas/química , Sobrevivência Celular , Fenômenos Eletromagnéticos , Álcoois Graxos/química , Células HeLa , Humanos , Microscopia Eletrônica de Transmissão , Nanopartículas/ultraestrutura , Ácido Oleico/química , Espectroscopia de Infravermelho com Transformada de Fourier , Temperatura , Difração de Raios X
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