Improved pharmacokinetics and bone tissue accumulation of Angiotensin-(1-7) peptide through bisphosphonate conjugation.
Amino Acids
; 53(5): 653-664, 2021 May.
Article
en En
| MEDLINE
| ID: mdl-33791863
ABSTRACT
The renin-angiotensin system (RAS) has a central role in renal and cardiovascular homeostasis. Angiotensin-(1-7) (Ang1-7), one of the RAS active peptides, exerts beneficial effects through different mechanisms. These biological actions suggest that Ang1-7 is an effective therapeutic agent for treating various diseases associated with activated RAS. However, its short half-life and poor pharmacokinetics restrict its therapeutic utility. Our laboratory has successfully synthesized and characterized an Ang1-7 conjugate (Ang Conj.) with a prolonged half-life and improved pharmacokinetics profile. The Ang Conj. has been prepared by PEGylation of Ang1-7 and conjugation with a bisphosphonate using solid-phase peptide synthesis and characterized by HPLC and mass spectrometer. The compound's stability has been tested in different storage conditions. The bone binding capacity was evaluated using a hydroxyapatite assay. Pharmacokinetic and tissue distribution studies were performed using iodinated peptides in rats. Ang Conj. was synthesized with > 90% purity. Bone mineral affinity testing showed Ang Conj. exhibited significantly higher bone mineral affinity than Ang1-7. The Ang Conj. remained stable for more than a month using all tested storage conditions. The Ang Conj. demonstrated higher affinity to bone, a longer half-life, and better bioavailability when compared with the native peptide. These results support that conjugation of Ang1-7 with bisphosphonate enables it to utilize bone as a reservoir for the sustained delivery of Ang1-7 to maintain therapeutic plasma levels. High chemical stability and about five to tenfold prolongation of Ang Conj. plasma half-life after administrations into rats proves the effectiveness of our approach.
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Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Fragmentos de Péptidos
/
Huesos
/
Angiotensina I
/
Difosfonatos
Límite:
Animals
Idioma:
En
Revista:
Amino Acids
Asunto de la revista:
BIOQUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos