Márquez-Miranda Valeria, Abrigo Johanna, Rivera Juan Carlos, Araya-Durán Ingrid, Aravena Javier, Simon Felipe, Pacheco Nicolás, González-Nilo Fernando Danilo, Cabello-Verrugio Claudio
Center for Bioinformatics and Integrative Biology (CBIB), Facultad de Ciencias Biologicas, Universidad Andres Bello, Santiago; Fundación Fraunhofer Chile Research, Las Condes.
Departamento de Ciencias Biologicas, Facultad de Ciencias Biologicas & Facultad de Medicina, Universidad Andres Bello; Millennium Institute on Immunology and Immunotherapy, Santiago.
Int J Nanomedicine. 2017 Mar 13;12:1985-1999. doi: 10.2147/IJN.S125521. eCollection 2017.
Angiotensin (1-7) (Ang-(1-7)) is a bioactive heptapeptide with a short half-life and has beneficial effects in several tissues - among them, skeletal muscle - by preventing muscle atrophy. Dendrimers are promising vehicles for the protection and transport of numerous bioactive molecules. This work explored the use of a neutral, non-cytotoxic hydroxyl-terminated poly(amidoamine) (PAMAM-OH) dendrimer as an Ang-(1-7) carrier. Bioinformatics analysis showed that the Ang-(1-7)-binding capacity of the dendrimer presented a 2:1 molar ratio. Molecular dynamics simulation analysis revealed the capacity of neutral PAMAM-OH to protect Ang-(1-7) and form stable complexes. The peptide coverage ability of the dendrimer was between ~50% and 65%. Furthermore, an electrophoretic mobility shift assay demonstrated that neutral PAMAM-OH effectively bonded peptides. Experimental results showed that the Ang-(1-7)/PAMAM-OH complex, but not Ang-(1-7) alone, had an anti-atrophic effect when administered intraperitoneally, as evaluated by muscle strength, fiber diameter, myofibrillar protein levels, and atrogin-1 and MuRF-1 expressions. The results of the Ang-(1-7)/PAMAM-OH complex being intraperitoneally injected were similar to the results obtained when Ang-(1-7) was systemically administered through mini-osmotic pumps. Together, the results suggest that Ang-(1-7) can be protected for PAMAM-OH when this complex is intraperitoneally injected. Therefore, the Ang-(1-7)/PAMAM-OH complex is an efficient delivery method for Ang-(1-7), since it improves the anti-atrophic activity of this peptide in skeletal muscle.
血管紧张素(1-7)(Ang-(1-7))是一种半衰期较短的生物活性七肽,通过预防肌肉萎缩,对包括骨骼肌在内的多种组织具有有益作用。树枝状大分子是用于保护和运输众多生物活性分子的有前景的载体。这项工作探索了使用中性、无细胞毒性的羟基封端聚(酰胺胺)(PAMAM-OH)树枝状大分子作为Ang-(1-7)的载体。生物信息学分析表明,树枝状大分子与Ang-(1-7)的结合能力呈现2:1的摩尔比。分子动力学模拟分析揭示了中性PAMAM-OH保护Ang-(1-7)并形成稳定复合物的能力。树枝状大分子的肽覆盖能力在约50%至65%之间。此外,电泳迁移率变动分析表明中性PAMAM-OH能有效结合肽。实验结果表明,通过肌肉力量、纤维直径、肌原纤维蛋白水平以及atrogin-1和MuRF-1表达评估,腹腔注射时,Ang-(1-7)/PAMAM-OH复合物而非单独的Ang-(1-7)具有抗萎缩作用。腹腔注射Ang-(1-7)/PAMAM-OH复合物的结果与通过微型渗透泵全身给药Ang-(1-7)时获得的结果相似。总之,结果表明腹腔注射该复合物时,Ang-(1-7)可被PAMAM-OH保护。因此,Ang-(1-7)/PAMAM-OH复合物是一种有效的Ang-(1-7)递送方法,因为它提高了该肽在骨骼肌中的抗萎缩活性。
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