Estudo in silico da co-formulação de insulina com amilina e seus análogos biotecnológicos
Diabetes is a disease resulting from a deficiency in insulin production or resistance to its action. In type one diabetes, the patient is already born with the disease hereditarily, while on type two, its genesis occurs as a result of other factors and habits that contribute to the appearance of thi...
| Autor principal: | Rodrigues, Fabio |
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| Formato: | Dissertação |
| Idioma: | Português |
| Publicado em: |
Universidade Tecnológica Federal do Paraná
2020
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| Assuntos: | |
| Acesso em linha: |
http://repositorio.utfpr.edu.br/jspui/handle/1/5207 |
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| Resumo: |
Diabetes is a disease resulting from a deficiency in insulin production or resistance to its action. In type one diabetes, the patient is already born with the disease hereditarily, while on type two, its genesis occurs as a result of other factors and habits that contribute to the appearance of this organic dysfunction, such as obesity and sedentary lifestyle, for example, which are acquired by poor diet, caused mainly by excessive intake of carbohydrates and fats, combined with a lack of physical activities. The disease is controlled by monitoring the glycemic level and using insulin injections, which causes discomfort for the patient, in addition to resulting in a cycle of weight gain and insulin resistance. Human amylin (hIAPP) is another hormone that acts on metabolic regulation along with insulin. However, due to its amyloidogenic profile, that is, it aggregates and forms insoluble fibrils, a hIAPP is inappropriate for co-use with insulin. This led to the development of new hIAPP analogs with improved characteristics, through amino acid substitution techniques, such as Pramlintide known as sIAPP, which is quantified by the replacement of an Alanine and two Serines, for Prolines ie (for example, A25P, S28P, S29P). Thus, sIAPP presents a significant increase in resistance to aggregation. But there is still the problem of low solubility of sIAPP at physiological pHs. This problem has been studied recently and led to the creation of the sIAPP+: that is, an extra replacement of a Serine with na Arginine at position 20 (i.e, S20R) of the sIAPP sequence. In this work, we developed a comparative theoretical study in silicon using Amylin and its analogues (i.e, hIAPP, sIAPP and sIAPP+) in order to test the effectiveness of its coformulations with insulin. In our methodology, we evaluated the stability of these formulations using data extracted from the microcanonical stage of multicanonical simulations of insulin co-formulation with Amylin analogs. Thus, we calculate thermodynamic quantities, such as latent heat and free-energy aggregation barriers, evaluate the results and theoretically verify the physical-chemical stability. We also analyze the phase transitions and their respective aggregation times. Our results are complemented with energy calculations of solvation and structural analysis. |
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