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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

Cell Apoptosis of CGC exposed to hIAPP20–29, in monomeric and aggregated form, with and without N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine D; methyl (2-{[4-(1-naphthylamino)-4-oxobutanoyl]amino}ethyl) dithiocarbamate B and H used as reference; at different molar ratio hIAPP20–29:chaperones.In all assays caspase-3 levels were measured by immunofluorescence.
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pone.0135292.g011: Cell Apoptosis of CGC exposed to hIAPP20–29, in monomeric and aggregated form, with and without N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine D; methyl (2-{[4-(1-naphthylamino)-4-oxobutanoyl]amino}ethyl) dithiocarbamate B and H used as reference; at different molar ratio hIAPP20–29:chaperones.In all assays caspase-3 levels were measured by immunofluorescence.

Mentions: In the case of the aggregated form of hIAPP20–29 in presence of chaperone D, the CGC viability did not differ significantly from cells exposed to hIAPP20–29 (p >0.05). As expected, H showed a marked cytoprotective effect that differed statistically from chaperones B and D (p <0.05). Fig 11 shows the results of the cell apoptosis assays, in which the level of caspase-3 was measured by an immunofluorescence assay. The caspase-3 levels of CGC exposed to monomeric or aggregated hIAPP20–29 were not significantly different between them (p >0.05) and they were the highest apoptotic levels observed. Contrastingly, in presence of chaperones, the caspase-3 levels of CGC exposed to hIAPP20–29 diminished (p <0.05).


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)

Cell Apoptosis of CGC exposed to hIAPP20–29, in monomeric and aggregated form, with and without N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine D; methyl (2-{[4-(1-naphthylamino)-4-oxobutanoyl]amino}ethyl) dithiocarbamate B and H used as reference; at different molar ratio hIAPP20–29:chaperones.In all assays caspase-3 levels were measured by immunofluorescence.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135292.g011: Cell Apoptosis of CGC exposed to hIAPP20–29, in monomeric and aggregated form, with and without N-[4-(1-naphthylamino)-4-oxobutanoyl]-β-alanine D; methyl (2-{[4-(1-naphthylamino)-4-oxobutanoyl]amino}ethyl) dithiocarbamate B and H used as reference; at different molar ratio hIAPP20–29:chaperones.In all assays caspase-3 levels were measured by immunofluorescence.
Mentions: In the case of the aggregated form of hIAPP20–29 in presence of chaperone D, the CGC viability did not differ significantly from cells exposed to hIAPP20–29 (p >0.05). As expected, H showed a marked cytoprotective effect that differed statistically from chaperones B and D (p <0.05). Fig 11 shows the results of the cell apoptosis assays, in which the level of caspase-3 was measured by an immunofluorescence assay. The caspase-3 levels of CGC exposed to monomeric or aggregated hIAPP20–29 were not significantly different between them (p >0.05) and they were the highest apoptotic levels observed. Contrastingly, in presence of chaperones, the caspase-3 levels of CGC exposed to hIAPP20–29 diminished (p <0.05).

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