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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

Proposal mechanism of chaperone on protein aggregation/disaggregation.Novel chemical chaperones family can regulate fiber formation processes by binding to the native state, minimizing the formation of amorphous aggregates, as well as cytotoxic oligomers.
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pone.0135292.g014: Proposal mechanism of chaperone on protein aggregation/disaggregation.Novel chemical chaperones family can regulate fiber formation processes by binding to the native state, minimizing the formation of amorphous aggregates, as well as cytotoxic oligomers.

Mentions: In this article, we show how by selecting compounds based on the two states of the amyloid protein (native and amyloid pharmacophore structure) we managed to obtain chaperones that bind to the native state, to the cytotoxic oligomers and to the amyloid fibrils (Figs 6, 9 and 14 and Table 1). The novel chemical chaperones can regulate fibril formation processes by binding to the native state, minimizing the formation of amorphous aggregates, as well as cytotoxic oligomers. It is worth mentioning that these compounds also adhere to the fibrils and stabilize them. Chaperone F in particular was found to accelerate the formation of hIAPP20–29 fibrils by binding to cytotoxic oligomers (Fig 7). In this article we demonstrate the physiopathological conditions in which a set of chaperones can be used. We observed that in acute processes, with abundance of cytotoxic oligomers, chaperone F is the most suitable for arresting the former, forming fibers and thus preventing apoptosis caused by membrane pores. For chronic processes, chaperones A, B, C and D were found to be apposite for stabilizing the monomer and reducing the formation of fibres (Table 1, Figs 5–14). This is extremely relevant as it allows for a close examination of the fiber-formation phenomena and, potentially, to control cytotoxicity. If taken to the next stage—assaying the dynamics of these chaperones in living organisms in order to learn their effects within cognitive and metabolic processes—this could lead to the development of therapeutic agents derived from this chaperone family that could help control the devastating effects of conformational diseases. Finally, the findings reported in this article are useful for encouraging research in reverse engineering, as well as building increasingly effective chemical libraries for the treatment of conformational diseases.


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)

Proposal mechanism of chaperone on protein aggregation/disaggregation.Novel chemical chaperones family can regulate fiber formation processes by binding to the native state, minimizing the formation of amorphous aggregates, as well as cytotoxic oligomers.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135292.g014: Proposal mechanism of chaperone on protein aggregation/disaggregation.Novel chemical chaperones family can regulate fiber formation processes by binding to the native state, minimizing the formation of amorphous aggregates, as well as cytotoxic oligomers.
Mentions: In this article, we show how by selecting compounds based on the two states of the amyloid protein (native and amyloid pharmacophore structure) we managed to obtain chaperones that bind to the native state, to the cytotoxic oligomers and to the amyloid fibrils (Figs 6, 9 and 14 and Table 1). The novel chemical chaperones can regulate fibril formation processes by binding to the native state, minimizing the formation of amorphous aggregates, as well as cytotoxic oligomers. It is worth mentioning that these compounds also adhere to the fibrils and stabilize them. Chaperone F in particular was found to accelerate the formation of hIAPP20–29 fibrils by binding to cytotoxic oligomers (Fig 7). In this article we demonstrate the physiopathological conditions in which a set of chaperones can be used. We observed that in acute processes, with abundance of cytotoxic oligomers, chaperone F is the most suitable for arresting the former, forming fibers and thus preventing apoptosis caused by membrane pores. For chronic processes, chaperones A, B, C and D were found to be apposite for stabilizing the monomer and reducing the formation of fibres (Table 1, Figs 5–14). This is extremely relevant as it allows for a close examination of the fiber-formation phenomena and, potentially, to control cytotoxicity. If taken to the next stage—assaying the dynamics of these chaperones in living organisms in order to learn their effects within cognitive and metabolic processes—this could lead to the development of therapeutic agents derived from this chaperone family that could help control the devastating effects of conformational diseases. Finally, the findings reported in this article are useful for encouraging research in reverse engineering, as well as building increasingly effective chemical libraries for the treatment of conformational diseases.

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