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1.
PLoS One ; 17(10): e0269437, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36227868

RESUMO

The visual cycle refers to a series of biochemical reactions of retinoids in ocular tissues and supports the vision in vertebrates. The visual cycle regenerates visual pigments chromophore, 11-cis-retinal, and eliminates its toxic byproducts from the retina, supporting visual function and retinal neuron survival. Unfortunately, during the visual cycle, when 11-cis-retinal is being regenerated in the retina, toxic byproducts, such as all-trans-retinal and bis-retinoid is N-retinylidene-N-retinylethanolamine (A2E), are produced, which are proposed to contribute to the pathogenesis of the dry form of age-related macular degeneration (AMD). The primary biochemical defect in Stargardt disease (STGD1) is the accelerated synthesis of cytotoxic lipofuscin bisretinoids, such as A2E, in the retinal pigment epithelium (RPE) due to mutations in the ABCA4 gene. To prevent all-trans-retinal-and bisretinoid-mediated retinal degeneration, slowing down the retinoid flow by modulating the visual cycle with a small molecule has been proposed as a therapeutic strategy. The present study describes RPE65-61, a novel, non-retinoid compound, as an inhibitor of RPE65 (a key enzyme in the visual cycle), intended to modulate the excessive activity of the visual cycle to protect the retina from harm degenerative diseases. Our data demonstrated that (±)-RPE65-61 selectively inhibited retinoid isomerase activity of RPE65, with an IC50 of 80 nM. Furthermore, (±)-RPE65-61 inhibited RPE65 via an uncompetitive mechanism. Systemic administration of (±)-RPE65-61 in mice resulted in slower chromophore regeneration after light bleach, confirming in vivo target engagement and visual cycle modulation. Concomitant protection of the mouse retina from high-intensity light damage was also observed. Furthermore, RPE65-61 down-regulated the cyclic GMP-AMP synthase stimulator of interferon genes (cGAS-STING) pathway, decreased the inflammatory factor, and attenuated retinal apoptosis caused by light-induced retinal damage (LIRD), which led to the preservation of the retinal function. Taken together, (±)-RPE65-61 is a potent visual cycle modulator that may provide a neuroprotective therapeutic benefit for patients with STGD and AMD.


Assuntos
Degeneração Macular , Degeneração Retiniana , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Interferons/metabolismo , Lipofuscina/metabolismo , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Camundongos , Nucleotidiltransferases/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/etiologia , Degeneração Retiniana/prevenção & controle , Pigmentos da Retina/metabolismo , Retinaldeído/metabolismo , Retinaldeído/farmacologia , Retinoides/metabolismo , Retinoides/farmacologia , cis-trans-Isomerases/genética , cis-trans-Isomerases/metabolismo
2.
J Med Chem ; 64(13): 9010-9041, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34138572

RESUMO

Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of proamyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener (14) that exhibits excellent TTR tetramer binding potency, prevents TTR aggregation in a gel-based assay, and possesses desirable pharmacokinetics in mice. Additionally, 14 significantly lowers murine serum retinol binding protein 4 (RBP4) levels despite a lack of binding at that protein's all-trans-retinol site. We hypothesize that kinetic stabilization of TTR tetramers via 14 is allosterically hindering all-trans-retinol-dependent RBP4-TTR tertiary complex formation and that the compound could present ancillary therapeutic utility for indications treated with RBP4 antagonists, such as macular degeneration.


Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Pré-Albumina/farmacologia , Proteínas Plasmáticas de Ligação ao Retinol/antagonistas & inibidores , Neuropatias Amiloides Familiares/metabolismo , Animais , Relação Dose-Resposta a Droga , Cinética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Estrutura Molecular , Pré-Albumina/síntese química , Pré-Albumina/química , Proteínas Plasmáticas de Ligação ao Retinol/deficiência , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Relação Estrutura-Atividade
3.
J Med Chem ; 63(19): 11054-11084, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-32878437

RESUMO

Accumulation of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)-transthyretin (TTR)-retinol complex. We previously identified selective RBP4 antagonists that dissociate circulating RBP4-TTR-retinol complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis in models of enhanced retinal lipofuscinogenesis. However, the release of TTR by selective RBP4 antagonists may be associated with TTR tetramer destabilization and, potentially, TTR amyloid formation. We describe herein the identification of bispecific RBP4 antagonist-TTR tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based assay. This new class of bispecific compounds may be especially important as a therapy for dry AMD patients who have another common age-related comorbidity, senile systemic amyloidosis, a nongenetic disease associated with wild-type TTR misfolding.


Assuntos
Biopolímeros/metabolismo , Desenho de Fármacos , Atrofia Geográfica/tratamento farmacológico , Degeneração Macular/tratamento farmacológico , Pré-Albumina/metabolismo , Proteínas Plasmáticas de Ligação ao Retinol/antagonistas & inibidores , Animais , Biopolímeros/química , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Atrofia Geográfica/metabolismo , Humanos , Degeneração Macular/metabolismo , Camundongos , Estrutura Molecular , Pré-Albumina/química , Proteínas Plasmáticas de Ligação ao Retinol/química
4.
ACS Chem Neurosci ; 11(9): 1250-1258, 2020 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-32191428

RESUMO

Glycine neurotransmission in the dorsal horn of the spinal cord plays a key role in regulating nociceptive signaling, but in chronic pain states reduced glycine neurotransmission is associated with the development of allodynia and hypersensitivity to painful stimuli. This suggests that restoration of glycine neurotransmission may be therapeutic for the treatment of chronic pain. Glycine transporter 2 inhibitors have been demonstrated to enhance glycine neurotransmission and provide relief from allodynia in rodent models of chronic pain. In recent years, photoswitchable compounds have been developed to provide the possibility of controlling the activity of target proteins using light. In this study we have developed a photoswitchable noncompetitive inhibitor of glycine transporter 2 that has different affinities for the transporter at 365 nm compared to 470 nm light.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina , Hiperalgesia , Benzamidas , Humanos , Medula Espinal
5.
PLoS One ; 14(10): e0224094, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31648246

RESUMO

Francisella tularensis is a Gram-negative bacterium responsible for causing tularemia in the northern hemisphere. F. tularensis has long been developed as a biological weapon due to its ability to cause severe illness upon inhalation of as few as ten organisms and, based on its potential to be used as a bioterror agent is now classified as a Tier 1 Category A select agent by the CDC. The stringent response facilitates bacterial survival under nutritionally challenging starvation conditions. The hallmark of stringent response is the accumulation of the effector molecules ppGpp and (p)ppGpp known as stress alarmones. The relA and spoT gene products generate alarmones in several Gram-negative bacterial pathogens. RelA is a ribosome-associated ppGpp synthetase that gets activated under amino acid starvation conditions whereas, SpoT is a bifunctional enzyme with both ppGpp synthetase and ppGpp hydrolase activities. Francisella encodes a monofunctional RelA and a bifunctional SpoT enzyme. Previous studies have demonstrated that stringent response under nutritional stresses increases expression of virulence-associated genes encoded on Francisella Pathogenicity Island. This study investigated how stringent response governs the oxidative stress response of F. tularensis. We demonstrate that RelA/SpoT-mediated ppGpp production alters global gene transcriptional profile of F. tularensis in the presence of oxidative stress. The lack of stringent response in relA/spoT gene deletion mutants of F. tularensis makes bacteria more susceptible to oxidants, attenuates survival in macrophages, and virulence in mice. This work is an important step forward towards understanding the complex regulatory network underlying the oxidative stress response of F. tularensis.


Assuntos
Proteínas de Bactérias/metabolismo , Francisella tularensis/fisiologia , Macrófagos/microbiologia , Estresse Oxidativo , Tularemia/microbiologia , Virulência , Animais , Proteínas de Bactérias/genética , Regulação Bacteriana da Expressão Gênica , Ligases/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ribossomos , Tularemia/epidemiologia
6.
Biochim Biophys Acta Mol Basis Dis ; 1864(7): 2420-2429, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29684583

RESUMO

The retinoid visual cycle is an ocular retinoid metabolism specifically dedicated to support vertebrate vision. The visual cycle serves not only to generate light-sensitive visual chromophore 11-cis-retinal, but also to clear toxic byproducts of normal visual cycle (i.e. all-trans-retinal and its condensation products) from the retina, ensuring both the visual function and the retinal health. Unfortunately, various conditions including genetic predisposition, environment and aging may attribute to a functional decline of the all-trans-retinal clearance. To combat all-trans-retinal mediated retinal degeneration, we sought to slow down the retinoid influx from the RPE by inhibiting the visual cycle with a small molecule. The present study describes identification of CU239, a novel non-retinoid inhibitor of RPE65, a key enzyme in the visual cycle. Our data demonstrated that CU239 selectively inhibited isomerase activity of RPE65, with IC50 of 6 µM. Further, our results indicated that CU239 inhibited RPE65 via competition with its substrate all-trans-retinyl ester. Mice with systemic injection of CU239 exhibited delayed chromophore regeneration after light bleach, and conferred a partial protection of the retina against injury from high intensity light. Taken together, CU239 is a potent visual cycle modulator and may have a therapeutic potential for retinal degeneration.


Assuntos
Inibidores Enzimáticos/farmacologia , Degeneração Retiniana , Visão Ocular , cis-trans-Isomerases , Animais , Diterpenos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Degeneração Retiniana/tratamento farmacológico , Degeneração Retiniana/enzimologia , Degeneração Retiniana/genética , Degeneração Retiniana/patologia , Ésteres de Retinil , Visão Ocular/efeitos dos fármacos , Visão Ocular/genética , Vitamina A/análogos & derivados , Vitamina A/metabolismo , cis-trans-Isomerases/antagonistas & inibidores , cis-trans-Isomerases/genética , cis-trans-Isomerases/metabolismo
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