Hemocompatible L-Type amino acid transporter 1 (LAT1)-Utilizing prodrugs of perforin inhibitors can accumulate into the pancreas and alleviate inflammation-induced apoptosis.
Chem Biol Interact
; 345: 109560, 2021 Aug 25.
Article
em En
| MEDLINE
| ID: mdl-34153225
ABSTRACT
Cytolytic pore-forming protein, perforin, has been associated with autoimmune destruction of pancreatic ß-cells in type 1 diabetes mellitus (T1DM) once released from CD8+ T cells. Curiously, perforinopathy has also been implicated in numerous brain diseases. Therefore, inhibitors of perforin have been in demand with targeted delivery in mind. l-Type amino acid transporter 1 (LAT1) is known to be expressed in both the above-mentioned target tissues, in the pancreas as well as in the brain. Thus, in the present study, the distribution of two LAT1-utilizing prodrugs of investigational perforin inhibitors into the pancreas was explored after intraperitoneal (i.p., 30 µmol/kg) bolus injection to mice. The effects of prodrug 1 were also studied in lipopolysaccharide (LPS)-induced in vitro (50 µg/mL) and in vivo (250 µg/kg x 3 days) apoptosis and pancreatitis models by determining the cellular apoptotic levels with human umbilical vein endothelial cells (HUVEC) and pancreatic caspase-3/-7 activity in mice. Furthermore, the biocompatibility of prodrug 1 was explored in human plasma and towards red blood cells. According to the results, both prodrugs were accumulated more effectively into the pancreas than their parent drugs (in addition to the brain that has been previously reported). Prodrug 1 (30 µmol/kg) also decreased the pancreatic caspase-3/-7 activity (52%) and with 2.5 µM concentration, the number of early and late apoptotic cells (32-53%). Since prodrug 1 was also found to be hemocompatible and not affecting human plasma hemostasis or inducing hemolysis of erythrocytes at the concentration <50 µM, it can be considered biocompatible in systemic circulation and ready to be studied in the future as a dual-acting drug candidate (in the pancreas and brain) in diseases like T1DM with neurodegenerative comorbidities.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
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Apoptose
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Transportador 1 de Aminoácidos Neutros Grandes
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Perforina
Limite:
Animals
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Humans
Idioma:
En
Revista:
Chem Biol Interact
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Finlândia