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Drug Development in Conformational Diseases: A Novel Family of Chemical Chaperones that Bind and Stabilise Several Polymorphic Amyloid Structures.

Sablón-Carrazana M, Fernández I, Bencomo A, Lara-Martínez R, Rivera-Marrero S, Domínguez G, Pérez-Perera R, Jiménez-García LF, Altamirano-Bustamante NF, Diaz-Delgado M, Vedrenne F, Rivillas-Acevedo L, Pasten-Hidalgo K, Segura-Valdez Mde L, Islas-Andrade S, Garrido-Magaña E, Perera-Pintado A, Prats-Capote A, Rodríguez-Tanty C, Altamirano-Bustamante MM - PLoS ONE (2015)

Bottom Line: It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system.Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP20-29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers.In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes.

View Article: PubMed Central - PubMed

Affiliation: Dpto. Neurodiagnóstico, Centro de Neurociencias de Cuba, Cubanacán, Playa, La Habana, Cuba; Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.

ABSTRACT
The increasing prevalence of conformational diseases, including Alzheimer's disease, type 2 Diabetes Mellitus and Cancer, poses a global challenge at many different levels. It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system. In this work, we apply a cross-functional approach that combines ideas, concepts and technologies from several disciplines in order to study, in silico and in vitro, the role of a novel chemical chaperones family (NCHCHF) in processes of protein aggregation in conformational diseases. Given that Serum Albumin (SA) is the most abundant protein in the blood of mammals, and Bovine Serum Albumin (BSA) is an off-the-shelf protein available in most labs around the world, we compared the ligandability of BSA:NCHCHF with the interaction sites in the Human Islet Amyloid Polypeptide (hIAPP):NCHCHF, and in the amyloid pharmacophore fragments (Aβ17-42 and Aβ16-21):NCHCHF. We posit that the merging of this interaction sites is a meta-structure of pharmacophore which allows the development of chaperones that can prevent protein aggregation at various states from: stabilizing the native state to destabilizing oligomeric state and protofilament. Furthermore to stabilize fibrillar structures, thus decreasing the amount of toxic oligomers in solution, as is the case with the NCHCHF. The paper demonstrates how a set of NCHCHF can be used for studying and potentially treating the various physiopathological stages of a conformational disease. For instance, when dealing with an acute phase of cytotoxicity, what is needed is the recruitment of cytotoxic oligomers, thus chaperone F, which accelerates fiber formation, would be very useful; whereas in a chronic stage it is better to have chaperones A, B, C, and D, which stabilize the native and fibril structures halting self-catalysis and the creation of cytotoxic oligomers as a consequence of fiber formation. Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP20-29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers. In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes.

No MeSH data available.


Related in: MedlinePlus

Meta-structure of pharmacophore.A structural alignment using Pymol, whereby the interaction zones between β-amiloyd17–42 (Aβ17–42), IAPP and Eisenberg’s pharmacophore molecules and the chaperons were set in position with the interaction zone between BSA and the chaperons. BSA is shown in white at 70% transparency, the interaction zone between the Aβ17–42 and the chaperons is shown in red, the one corresponding to the Eisenberg pharmacophore in blue, with IAPP in yellow and with BSA in green.
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pone.0135292.g005: Meta-structure of pharmacophore.A structural alignment using Pymol, whereby the interaction zones between β-amiloyd17–42 (Aβ17–42), IAPP and Eisenberg’s pharmacophore molecules and the chaperons were set in position with the interaction zone between BSA and the chaperons. BSA is shown in white at 70% transparency, the interaction zone between the Aβ17–42 and the chaperons is shown in red, the one corresponding to the Eisenberg pharmacophore in blue, with IAPP in yellow and with BSA in green.

Mentions: Protein-ligand docking is the most intuitive and powerful tool for structure-based drug discovery. Using protein-structure similarity clustering, as described by Waldmann and co-workers [32–36], we identified the conservation of structural motifs in the binding region of four target proteins (BSA, Aβ17–42, hIAPP1–37 and Aβ16–21, the two last data no shown) with the chaperones as ligands. First, the interaction zones of each of them were identified. So, structural alignment using Pymol was performed between each building blocks and root mean square deviation values (RMSD ‹ 3Å) were obtained for each case. These low RMSD values indicated the 3D structural similarity of the interaction sites between all proteins simulated (Fig 5). This means that the conservation of the structural motifs, as the ligand recognizing area, allows us to target these regions, which can well be called a “meta-structure” viewed as an intricate network of interacting residues in a topological space, according to Konrat et. Co-workers [35,36]. In sum, this strategy follows the principle that identifying meta-structure similarities in ligand interaction sites is a reliable method for discovery chemical scaffolding which serve as guides toward the development of new drugs. Moreover, it is possible to speak of a “meta-pharmacophore” that allows the development of compounds that prevent aggregation at different stages; that is to say, from stabilizing the native state to destabilizing the oligomeric state and protofilament formation, which is the case of interest to this paper.


Drug Development in Conformational Diseases: A Novel Family of Chemical Chaperones that Bind and Stabilise Several Polymorphic Amyloid Structures.

Sablón-Carrazana M, Fernández I, Bencomo A, Lara-Martínez R, Rivera-Marrero S, Domínguez G, Pérez-Perera R, Jiménez-García LF, Altamirano-Bustamante NF, Diaz-Delgado M, Vedrenne F, Rivillas-Acevedo L, Pasten-Hidalgo K, Segura-Valdez Mde L, Islas-Andrade S, Garrido-Magaña E, Perera-Pintado A, Prats-Capote A, Rodríguez-Tanty C, Altamirano-Bustamante MM - PLoS ONE (2015)

Meta-structure of pharmacophore.A structural alignment using Pymol, whereby the interaction zones between β-amiloyd17–42 (Aβ17–42), IAPP and Eisenberg’s pharmacophore molecules and the chaperons were set in position with the interaction zone between BSA and the chaperons. BSA is shown in white at 70% transparency, the interaction zone between the Aβ17–42 and the chaperons is shown in red, the one corresponding to the Eisenberg pharmacophore in blue, with IAPP in yellow and with BSA in green.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556714&req=5

pone.0135292.g005: Meta-structure of pharmacophore.A structural alignment using Pymol, whereby the interaction zones between β-amiloyd17–42 (Aβ17–42), IAPP and Eisenberg’s pharmacophore molecules and the chaperons were set in position with the interaction zone between BSA and the chaperons. BSA is shown in white at 70% transparency, the interaction zone between the Aβ17–42 and the chaperons is shown in red, the one corresponding to the Eisenberg pharmacophore in blue, with IAPP in yellow and with BSA in green.
Mentions: Protein-ligand docking is the most intuitive and powerful tool for structure-based drug discovery. Using protein-structure similarity clustering, as described by Waldmann and co-workers [32–36], we identified the conservation of structural motifs in the binding region of four target proteins (BSA, Aβ17–42, hIAPP1–37 and Aβ16–21, the two last data no shown) with the chaperones as ligands. First, the interaction zones of each of them were identified. So, structural alignment using Pymol was performed between each building blocks and root mean square deviation values (RMSD ‹ 3Å) were obtained for each case. These low RMSD values indicated the 3D structural similarity of the interaction sites between all proteins simulated (Fig 5). This means that the conservation of the structural motifs, as the ligand recognizing area, allows us to target these regions, which can well be called a “meta-structure” viewed as an intricate network of interacting residues in a topological space, according to Konrat et. Co-workers [35,36]. In sum, this strategy follows the principle that identifying meta-structure similarities in ligand interaction sites is a reliable method for discovery chemical scaffolding which serve as guides toward the development of new drugs. Moreover, it is possible to speak of a “meta-pharmacophore” that allows the development of compounds that prevent aggregation at different stages; that is to say, from stabilizing the native state to destabilizing the oligomeric state and protofilament formation, which is the case of interest to this paper.

Bottom Line: It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system.Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP20-29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers.In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes.

View Article: PubMed Central - PubMed

Affiliation: Dpto. Neurodiagnóstico, Centro de Neurociencias de Cuba, Cubanacán, Playa, La Habana, Cuba; Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.

ABSTRACT
The increasing prevalence of conformational diseases, including Alzheimer's disease, type 2 Diabetes Mellitus and Cancer, poses a global challenge at many different levels. It has devastating effects on the sufferers as well as a tremendous economic impact on families and the health system. In this work, we apply a cross-functional approach that combines ideas, concepts and technologies from several disciplines in order to study, in silico and in vitro, the role of a novel chemical chaperones family (NCHCHF) in processes of protein aggregation in conformational diseases. Given that Serum Albumin (SA) is the most abundant protein in the blood of mammals, and Bovine Serum Albumin (BSA) is an off-the-shelf protein available in most labs around the world, we compared the ligandability of BSA:NCHCHF with the interaction sites in the Human Islet Amyloid Polypeptide (hIAPP):NCHCHF, and in the amyloid pharmacophore fragments (Aβ17-42 and Aβ16-21):NCHCHF. We posit that the merging of this interaction sites is a meta-structure of pharmacophore which allows the development of chaperones that can prevent protein aggregation at various states from: stabilizing the native state to destabilizing oligomeric state and protofilament. Furthermore to stabilize fibrillar structures, thus decreasing the amount of toxic oligomers in solution, as is the case with the NCHCHF. The paper demonstrates how a set of NCHCHF can be used for studying and potentially treating the various physiopathological stages of a conformational disease. For instance, when dealing with an acute phase of cytotoxicity, what is needed is the recruitment of cytotoxic oligomers, thus chaperone F, which accelerates fiber formation, would be very useful; whereas in a chronic stage it is better to have chaperones A, B, C, and D, which stabilize the native and fibril structures halting self-catalysis and the creation of cytotoxic oligomers as a consequence of fiber formation. Furthermore, all the chaperones are able to protect and recondition the cerebellar granule cells (CGC) from the cytotoxicity produced by the hIAPP20-29 fragment or by a low potassium medium, regardless of their capacity for accelerating or inhibiting in vitro formation of fibers. In vivo animal experiments are required to study the impact of chemical chaperones in cognitive and metabolic syndromes.

No MeSH data available.


Related in: MedlinePlus