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1.
Bioorg Med Chem ; 29: 115871, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33221064

RESUMO

Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l-leucine to tRNALeu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of SpLeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure-activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS.


Assuntos
Antibacterianos/farmacologia , Compostos Benzidrílicos/farmacologia , Compostos de Boro/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/síntese química , Antibacterianos/química , Compostos Benzidrílicos/química , Compostos de Boro/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Leucina-tRNA Ligase , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Streptococcus pneumoniae/enzimologia , Relação Estrutura-Atividade
2.
Curr Issues Mol Biol ; 35: 17-34, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31422931

RESUMO

SUMOylation and DeSUMOylation are reversible protein post-translational modification (PTM) processes involving small ubiquitin-like modifier (SUMO) proteins. These processes have indispensable roles in various cellular processes, such as subcellular localization, gene transcription, and DNA replication and repair. Over the past decade, increasing attention has been given to SUMO-related pathways as potential therapeutic targets. The Sentrin/SUMO-specific protease (SENP), which is responsible for deSUMOylation, has been proposed as a potential therapeutic target in the treatment of cancers and cardiac disorders. Unfortunately, no SENP inhibitor has yet reached clinical trials. In this review, we focus on advances in the development of SENP inhibitors in the past decade.


Assuntos
Doenças Cardiovasculares/metabolismo , Cisteína Endopeptidases/metabolismo , Inibidores de Cisteína Proteinase/química , Neoplasias/metabolismo , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/metabolismo , Sumoilação , Animais , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/genética , Pontos de Checagem do Ciclo Celular/genética , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Inibidores de Cisteína Proteinase/metabolismo , Humanos , Terapia de Alvo Molecular , Neoplasias/enzimologia , Neoplasias/genética , Domínios Proteicos/genética , Processamento de Proteína Pós-Traducional/genética , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/química , Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina/genética
3.
Chembiochem ; 20(23): 2916-2920, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31219673

RESUMO

Photocontrol of protein activity is an emerging field in biomedicine. For optical control of a mutant small GTPase K-Ras(G12C), we developed small-molecule inhibitors with photoswitchable efficacy, where one configuration binds the target protein and exert different pharmacological effects upon light irradiation. The compound design was based on the structure feature of a previously identified allosteric pocket of K-Ras(G12C) and the chemical structure of covalent inhibitors, and resulted in the synthesis and characterization of two representative azobenzene-containing compounds. Nucleotide exchange assays demonstrated the different efficacy to control the GTP affinity by photoswitching of one potent compound PS-C2, which would be a useful tool to probe the conformation of mutational K-Ras. Our study demonstrated the feasibility of designing photoswitchable modulators from allosteric covalent inhibitor of small GTPases.


Assuntos
Acetanilidas/química , Compostos Azo/química , Guanosina Trifosfato/metabolismo , Ligação Proteica/efeitos dos fármacos , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Acetanilidas/síntese química , Acetanilidas/efeitos da radiação , Sítio Alostérico/efeitos dos fármacos , Compostos Azo/síntese química , Compostos Azo/efeitos da radiação , Mutação , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/genética , Estereoisomerismo , Raios Ultravioleta
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