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Molecules 2018, 23(3), 686; https://doi.org/10.3390/molecules23030686

Diabetes Drug Discovery: hIAPP1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets

1
Unidad de Investigación en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
2
Departamento de Neuroquímica, Centro de Neurociencias de Cuba, Habana 11600, Cuba
3
Instituto de Fisiología Celular, UNAM, Ciudad de México 04510, Mexico
4
Departamento de Biología Celular, Facultad de Ciencias, UNAM, Ciudad de México 04510, Mexico
5
Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico
6
Cátedras Conacyt, Instituto Nacional de Pediatría, Ciudad de México 04530, Mexico
7
Servicio de Medicina Nuclear, Hospital de Especialidades, CMN, La Raza, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
8
Coordinación de Investigación en Salud, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
9
UMAE Hospital de Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México 06720, Mexico
I.F.-G. and M.S.-C. contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 9 January 2018 / Revised: 20 February 2018 / Accepted: 21 February 2018 / Published: 19 March 2018
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Abstract

Human islet amyloid peptide (hIAPP1–37) aggregation is an early step in Diabetes Mellitus. We aimed to evaluate a family of pharmaco-chaperones to act as modulators that provide dynamic interventions and the multi-target capacity (native state, cytotoxic oligomers, protofilaments and fibrils of hIAPP1–37) required to meet the treatment challenges of diabetes. We used a cross-functional approach that combines in silico and in vitro biochemical and biophysical methods to study the hIAPP1–37 aggregation-oligomerization process as to reveal novel potential anti-diabetic drugs. The family of pharmaco-chaperones are modulators of the oligomerization and fibre formation of hIAPP1–37. When they interact with the amino acid in the amyloid-like steric zipper zone, they inhibit and/or delay the aggregation-oligomerization pathway by binding and stabilizing several amyloid structures of hIAPP1–37. Moreover, they can protect cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP1–37 oligomers. The modulation of proteostasis by the family of pharmaco-chaperones AF is a promising potential approach to limit the onset and progression of diabetes and its comorbidities. View Full-Text
Keywords: IAPP; diabetes mellitus; pharmacological chaperones; amyloid structures; conformational diseases; drug discovery IAPP; diabetes mellitus; pharmacological chaperones; amyloid structures; conformational diseases; drug discovery
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Fernández-Gómez, I.; Sablón-Carrazana, M.; Bencomo-Martínez, A.; Domínguez, G.; Lara-Martínez, R.; Altamirano-Bustamante, N.F.; Jiménez-García, L.F.; Pasten-Hidalgo, K.; Castillo-Rodríguez, R.A.; Altamirano, P.; Marrero, S.R.; Revilla-Monsalve, C.; Valdés-Sosa, P.; Salamanca-Gómez, F.; Garrido-Magaña, E.; Rodríguez-Tanty, C.; Altamirano-Bustamante, M.M. Diabetes Drug Discovery: hIAPP1–37 Polymorphic Amyloid Structures as Novel Therapeutic Targets. Molecules 2018, 23, 686.

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