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1.
Pharmaceutics ; 16(4)2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38675198

RESUMO

Teriparatide is an anabolic peptide drug indicated for the treatment of osteoporosis. Recombinant teriparatide was first approved in 2002 and has since been followed by patent-free alternatives under biosimilar or hybrid regulatory application. The aim of this study is to demonstrate the essential similarity between synthetic teriparatide BGW and the reference medicinal product (RMP), and thus to ensure the development of the first generic teriparatide drug. Hence, an extensive side-by-side comparative exercise, focusing on structural and biological activity, was performed using a wide range of state-of-the-art orthogonal methods. Nuclear magnetic resonance (NMR), ion mobility-mass spectrometry (IM-MS), UV, circular dichroism (CD) and Fourier transform infrared (FTIR) demonstrated the structural similarity between teriparatide BGW and the RMP. Comparative cell-based bioassays showed that the synthetic and recombinant peptides have identical behaviors. Teriparatide BGW, as a generic drug, provides an available treatment option for patients with osteoporosis and offers clinical benefits identical to those provided by the RMP.

2.
Cell Mol Life Sci ; 79(11): 546, 2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36221013

RESUMO

The majority of current cancer therapies are aimed at reducing tumour growth, but there is lack of viable pharmacological options to reduce the formation of metastasis. This is a paradox, since more than 90% of cancer deaths are attributable to metastatic progression. Integrin alpha9 (ITGA9) has been previously described as playing an essential role in metastasis; however, little is known about the mechanism that links this protein to this process, being one of the less studied integrins. We have now deciphered the importance of ITGA9 in metastasis and provide evidence demonstrating its essentiality for metastatic dissemination in rhabdomyosarcoma and neuroblastoma. However, the most translational advance of this study is to reveal, for the first time, the possibility of reducing metastasis by pharmacological inhibition of ITGA9 with a synthetic peptide simulating a key interaction domain of ADAM proteins, in experimental metastasis models, not only in childhood cancers but also in a breast cancer model.


Assuntos
Neuroblastoma , Rabdomiossarcoma , Proteínas ADAM/metabolismo , Humanos , Cadeias alfa de Integrinas , Integrinas , Metástase Neoplásica , Neuroblastoma/tratamento farmacológico , Rabdomiossarcoma/tratamento farmacológico
3.
Nat Commun ; 12(1): 1869, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767180

RESUMO

Ulcerative colitis and Crohn's disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment. Here, using NMR structural information, we design five Cortistatin analogues adopting selected native Cortistatin conformations in solution. One of them, A5, preserves the anti-inflammatory and immunomodulatory activities of Cortistatin in vitro and in mouse models of the disease. Additionally, A5 displays an increased half-life in serum and a unique receptor binding profile, thereby overcoming the limitations of the native Cortistatin as a therapeutic agent. This study provides an efficient approach to the rational design of Cortistatin analogues and opens up new possibilities for the treatment of patients that fail to respond to other therapies.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Imunomodulação/efeitos dos fármacos , Neuropeptídeos/uso terapêutico , Animais , Células Cultivadas , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Trato Gastrointestinal/patologia , Humanos , Inflamação/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Ácido Trinitrobenzenossulfônico/toxicidade
4.
Sci Rep ; 6: 27285, 2016 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-27271737

RESUMO

Somatostatin is a 14-residue peptide hormone that regulates the endocrine system by binding to five G-protein-coupled receptors (SSTR1-5). We have designed six new Somatostatin analogs with L-3-(3',5'-difluorophenyl)-alanine (Dfp) as a substitute of Phe and studied the effect of an electron-poor aromatic ring in the network of aromatic interactions present in Somatostatin. Replacement of each of the Phe residues (positions 6, 7 and 11) by Dfp and use of a D-Trp8 yielded peptides whose main conformations could be characterized in aqueous solution by NMR. Receptor binding studies revealed that the analog with Dfp at position 7 displayed a remarkable affinity to SSTR2 and SSTR3. Analogs with Dfp at positions 6 or 11 displayed a π-π interaction with the Phe present at 11 or 6, respectively. Interestingly, these analogs, particularly [D-Trp8,L-Dfp11]-SRIF, showed high selectivity towards SSTR2, with a higher value than that of Octreotide and a similar one to that of native Somatostatin.


Assuntos
Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/farmacologia , Somatostatina/análogos & derivados , Alanina/química , Sequência de Aminoácidos , Sítios de Ligação , Halogenação , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Estrutura Molecular , Peptídeos Cíclicos/química , Somatostatina/química , Relação Estrutura-Atividade
5.
J Med Chem ; 53(15): 5587-96, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20617807

RESUMO

The effects of lysine N(epsilon)-trimethylation at selected positions of the antimicrobial cecropin A-melittin hybrid peptide KWKLFKKIGAVLKVL-amide have been studied. All five monotrimethylated, four bis-trimethylated plus the per-trimethylated analogues have been synthesized and tested for antimicrobial activity on Leishmania parasites and on Gram-positive and -negative bacteria, as well as for hemolysis of sheep erythrocytes as a measure of cytotoxicity. The impact of trimethylation on the solution conformation of selected analogues has been evaluated by NMR, which indicates a slight decrease in the alpha-helical content of the modified peptides, particularly in the N-terminal region. Trimethylation also enhances the proteolytic stability of mono- and bis-trimethylated analogues by 2-3-fold. Although it tends to lower antimicrobial activity in absolute terms, trimethylation causes an even higher decrease in hemolytic activity and therefore results in improved selectivity for several analogues. The monotrimethylated analogue at position 6 shows the overall best selectivity against both the Leishmania donovani protozoan and Acinetobacter baumannii, a Gram-negative bacterium of increasing clinical concern.


Assuntos
Anti-Infecciosos/química , Peptídeos Catiônicos Antimicrobianos/química , Lisina/química , Sequência de Aminoácidos , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Infecciosos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Hemólise/efeitos dos fármacos , Leishmania/efeitos dos fármacos , Metilação , Modelos Moleculares , Conformação Molecular , Dados de Sequência Molecular , Relação Estrutura-Atividade , Tripanossomicidas/química , Tripanossomicidas/farmacologia
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