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1.
Org Lett ; 26(19): 4088-4092, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38709636

RESUMO

Access to 1,2,3-triazolium-grafted peptoid macrocycles was developed by macrocyclization and multivalent postmodification of linear peptoid oligomers carrying an alternance of benzylic and propargyl groups as side chains. X-ray analysis and NMR studies revealed a conformational preference for constrained hairpin-shaped structures leading to the facial amphipathic character of these macrocycles. A preliminary evaluation showed the antimicrobial activities of these new cationic amphipathic architectures.


Assuntos
Antibacterianos , Compostos Macrocíclicos , Testes de Sensibilidade Microbiana , Peptidomiméticos , Triazóis , Triazóis/química , Triazóis/farmacologia , Estrutura Molecular , Peptidomiméticos/química , Peptidomiméticos/farmacologia , Peptidomiméticos/síntese química , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Compostos Macrocíclicos/síntese química , Peptoides/química , Peptoides/farmacologia , Peptoides/síntese química , Cristalografia por Raios X , Bactérias/efeitos dos fármacos
2.
Sci Rep ; 12(1): 8146, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35581224

RESUMO

With the emergence of disease modifying osteoarthritis drugs (DMOAD), imaging methods to quantitatively demonstrate their efficacy and to monitor osteoarthritis progression at the functional level are urgently needed. Our group showed that articular cartilage can be quantitatively assessed in nuclear medicine imaging by our radiotracer 99mTc-NTP 15-5 targeting cartilage proteoglycans. In this work, surgically induced DMM mice were treated with sprifermin or saline. We investigated cartilage remodelling in the mice knees by 99mTc-NTP 15-5 SPECT-CT imaging over 24 weeks after surgery, as wells as proteoglycan biochemical assays. OA alterations were scored by histology according to OARSI guidelines. A specific accumulation of 99mTc-NTP 15-5 in cartilage joints was evidenced in vivo by SPECT-CT imaging as early as 30 min post-iv injection. In DMM, 99mTc-NTP 15-5 accumulation in cartilage within the operated joints, relative to contralateral ones, was observed to initially increase then decrease as pathology progressed. Under sprifermin, 99mTc-NTP 15-5 uptake in pathological knees was significantly increased compared to controls, at 7-, 12- and 24-weeks, and consistent with proteoglycan increase measured 5 weeks post-surgery, as a sign of cartilage matrix remodelling. Our work highlights the potential of 99mTc-NTP 15-5 as an imaging-based companion to monitor cartilage remodelling in OA and DMOAD response.


Assuntos
Cartilagem Articular , Osteoartrite , Animais , Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Modelos Animais de Doenças , Fatores de Crescimento de Fibroblastos , Compostos Heterocíclicos com 1 Anel , Indicadores e Reagentes , Camundongos , Osteoartrite/diagnóstico por imagem , Osteoartrite/tratamento farmacológico , Osteoartrite/patologia , Proteoglicanas , Compostos de Amônio Quaternário
3.
Cells ; 10(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34440743

RESUMO

The ubiquitin proteasome system (UPS) is the main player of skeletal muscle wasting, a common characteristic of many diseases (cancer, etc.) that negatively impacts treatment and life prognosis. Within the UPS, the E3 ligase MuRF1/TRIM63 targets for degradation several myofibrillar proteins, including the main contractile proteins alpha-actin and myosin heavy chain (MHC). We previously identified five E2 ubiquitin-conjugating enzymes interacting with MuRF1, including UBE2L3/UbcH7, that exhibited a high affinity for MuRF1 (KD = 50 nM). Here, we report a main effect of UBE2L3 on alpha-actin and MHC degradation in catabolic C2C12 myotubes. Consistently UBE2L3 knockdown in Tibialis anterior induced hypertrophy in dexamethasone (Dex)-treated mice, whereas overexpression worsened the muscle atrophy of Dex-treated mice. Using combined interactomic approaches, we also characterized the interactions between MuRF1 and its substrates alpha-actin and MHC and found that MuRF1 preferentially binds to filamentous F-actin (KD = 46.7 nM) over monomeric G-actin (KD = 450 nM). By contrast with actin that did not alter MuRF1-UBE2L3 affinity, binding of MHC to MuRF1 (KD = 8 nM) impeded UBE2L3 binding, suggesting that differential interactions prevail with MuRF1 depending on both the substrate and the E2. Our data suggest that UBE2L3 regulates contractile proteins levels and skeletal muscle atrophy.


Assuntos
Actinas/metabolismo , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Linhagem Celular , Dexametasona/farmacologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Ligação Proteica , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas com Motivo Tripartido/metabolismo , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Enzimas de Conjugação de Ubiquitina/genética , Ubiquitina-Proteína Ligases/metabolismo
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