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1.
Bioorg Med Chem ; 99: 117607, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38246114

RESUMO

Various tenofovir (TFV) prodrugs have been developed by introducing masking groups to the hydroxyls of the monophosphonate group to enhance intestinal absorption efficiency and therapeutic effects. However, the reported TFV prodrugs have drawbacks such as low bioavailability, systemic toxicity caused by their breakdown in non-targeted tissues, and potential low intracellular conversion efficiency. In the present study, we developed a class of TFV monobenzyl ester phosphonoamidate prodrugs without substitutions on the benzene ring. Compared with previous TFV prodrugs, compounds 3a and 3b developed in the present study showed higher anti-hepatitis B virus activity, stronger stability and higher levels of intrahepatic enrichment of the metabolic product (TFV), indicating the potential of these compounds as novel prodrugs with high efficiency and low systemic toxicity for the treatment of hepatitis B.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Pró-Fármacos , Humanos , Tenofovir/farmacologia , Tenofovir/metabolismo , Tenofovir/uso terapêutico , Fármacos Anti-HIV/uso terapêutico , Adenina/farmacologia , Adenina/uso terapêutico , Pró-Fármacos/metabolismo , Anticorpos , Infecções por HIV/tratamento farmacológico
2.
Biochemistry ; 59(49): 4646-4653, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33252220

RESUMO

We have validated that ligand peptides designed from antigen peptides could be used for targeting specific major histocompatibility complex class I (MHC-I) molecules on the cell surface. To design the ligand peptides, we used reported antigen peptides for each MHC-I molecule with high binding affinity. From the crystal structure of the peptide/MHC-I complexes, we determined a modifiable residue in the antigen peptides and replaced this residue with a lysine with an ε-amine group modified with functional molecules. The designed ligand peptides successfully bound to cells expressing the corresponding MHC-I molecules via exchange of peptides bound to MHC-I. We demonstrated that the peptide ligands could be used to transport a protein or a liposome to cells expressing the corresponding MHC-I. This strategy may be useful for targeted delivery to cells overexpressing MHC-I, which have been observed in autoimmune diseases.


Assuntos
Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Animais , Antígenos/química , Antígenos/metabolismo , Linhagem Celular , Membrana Celular/imunologia , Membrana Celular/metabolismo , Cristalografia por Raios X , Corantes Fluorescentes , Humanos , Ligantes , Lipossomos/química , Lipossomos/metabolismo , Camundongos , Modelos Moleculares , Peptídeos/síntese química , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Transporte Proteico
3.
Bioconjug Chem ; 28(2): 296-301, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28052667

RESUMO

We developed a strategy to modify cell membranes with an artificial transmembrane receptor. Coulomb force on the receptor, caused by the membrane potential, was used to achieve membrane penetration. A hydrophobically modified cationic peptide was used as a membrane potential sensitive region that was connected to biotin through a transmembrane oligoethylene glycol (OEG) chain. This artificial receptor gradually disappeared from the cell membrane via penetration despite the presence of a hydrophilic OEG chain. However, when the receptor was bound to streptavidin (SA), it remained on the cell membrane because of the large and hydrophilic nature of SA.


Assuntos
Membrana Celular/metabolismo , Potenciais da Membrana , Receptores Artificiais/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Espaço Intracelular/metabolismo , Células K562 , Polietilenoglicóis/química , Receptores Artificiais/química , Solubilidade , Estreptavidina/metabolismo , Água/química
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