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1.
J Med Chem ; 64(13): 9259-9270, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34160229

RESUMO

Tricyclic chemical structures are the core of many important drugs targeting all neurotransmitter pathways. These medicines enable effective therapies to treat from peptic ulcer disease to psychiatric disorders. However, when administered systemically, they cause serious adverse effects that limit their use. To obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimic the tricyclic chemical structure and display reversibly controlled activity. Pseudo-analogues of the tricyclic antagonist pirenzepine demonstrate that this is an effective strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both in vitro and in cardiac atria ex vivo. Despite the applied chemical modifications to make pirenzepine derivatives sensitive to light stimuli, the most potent candidate of the set, cryptozepine-2, maintained a moderate but promising M1 vs M2 subtype selectivity. These photoswitchable "crypto-azologs" of tricyclic drugs might open a general way to spatiotemporally target their therapeutic action while reducing their systemic toxicity and adverse effects.


Assuntos
Desenho de Fármacos , Antagonistas Muscarínicos/farmacologia , Pirenzepina/farmacologia , Receptores Muscarínicos/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Antagonistas Muscarínicos/síntese química , Antagonistas Muscarínicos/química , Pirenzepina/síntese química , Pirenzepina/química , Relação Estrutura-Atividade
2.
Chembiochem ; 22(10): 1800-1810, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33554411

RESUMO

The observables associated with protein intrinsic fluorescence - spectra, time decays, anisotropies - offer opportunities to monitor in real time and non-invasively a protein's functional form and its interchange with other forms with different functions. We employed these observables to sketch the fluorometric profiles of two functional forms of human thymidylate synthase (hTS), a homodimeric enzyme crucial for cell proliferation and thus targeted by anticancer drugs. The protein takes an active and an inactive form. Stabilization of the latter by peptides that, unlike classical hTS inhibitors, bind it at the monomer/monomer interface offers an alternative inhibition mechanism that promises to avoid the onset of drug resistance in anticancer therapy. The fluorescence features depicted herein can be used as tools to identify and quantify each of the two protein forms in solution, thus making it possible to investigate the kinetic and thermodynamic aspects of the active/inactive conformational interchange. Two examples of fluorometrically monitored interconversion kinetics are provided.


Assuntos
Polarização de Fluorescência , Timidilato Sintase/química , Nucleotídeos de Desoxiuracil/química , Nucleotídeos de Desoxiuracil/metabolismo , Humanos , Cinética , Simulação de Dinâmica Molecular , Mutagênese Sítio-Dirigida , Estrutura Quaternária de Proteína , Timidilato Sintase/genética , Timidilato Sintase/metabolismo
3.
J Med Chem ; 61(16): 7374-7380, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30035541

RESUMO

LR and [d-Gln4]LR peptides bind the monomer-monomer interface of human thymidylate synthase and inhibit cancer cell growth. Here, proline-mutated LR peptides were synthesized. Molecular dynamics calculations and circular dichroism spectra have provided a consistent picture of the conformational propensities of the [Pro n]-peptides. [Pro3]LR and [Pro4]LR show improved cell growth inhibition and similar intracellular protein modulation compared with LR. These represent a step forward to the identification of more rigid and metabolically stable peptides.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias Ovarianas/tratamento farmacológico , Peptídeos/farmacologia , Timidilato Sintase/antagonistas & inibidores , Antineoplásicos/química , Linhagem Celular Tumoral , Dicroísmo Circular , Inibidores Enzimáticos/química , Feminino , Humanos , Simulação de Dinâmica Molecular , Mutação , Neoplasias Ovarianas/patologia , Peptídeos/química , Peptídeos/genética , Prolina/genética , Conformação Proteica , Timidilato Sintase/genética , Timidilato Sintase/metabolismo
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