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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

Visualization of binding site of chaperones (A, B, C, D, E, F, G and H) into IIA and IIIA regions of BSA, within 5Å distance.
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pone.0135292.g003: Visualization of binding site of chaperones (A, B, C, D, E, F, G and H) into IIA and IIIA regions of BSA, within 5Å distance.

Mentions: The conformer with the lowest binding energy was calculated from 10 different conformations for each docking simulation, at 5 Å distance between chaperones and BSA (S1 Table). Finally, it was found that the chaperone-BSA binding site was located into the domain IIA and IIIA of the protein, which corresponds to the lowest free energy values calculated. According to the analysis of the calculated free energy, the binding process of BSA with chaperones is spontaneous (ΔG<0). The common amino acid residues lining this binding site were: His145, Glu186, Leu189, Thr190, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Ile455, Arg458 and Asp107, Ser109, Leu189, Thr190, Ala193, Arg196, Glu424, Ser428 Lys431, Val432, Arg435, Tyr451, Ile455, Arg458, for the 1G and 2G groups respectively. The compounds of the 3G group interact with the following common amino acid residues: Asp108, Glu186, Leu189, Thr190, Ser192, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Leu454, Ile455, and Arg458. Similarly, the binding amino acid residues for C and curcumin (H) are Glu186, Leu189, Thr190, Ser192, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Ile455, and Arg458. In 85% of calculations, the interaction zone was comprised between amino acids 145 to 458, specifically with the residues His145, Glu186, Leu189, Thr190, Ser192, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Ile455, and Arg458. In general, these molecules bind to the sites via hydrophobic and Van der Waals forces. In some cases, hydrogen-bonding interactions have been observed. (Fig 3).


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)

Visualization of binding site of chaperones (A, B, C, D, E, F, G and H) into IIA and IIIA regions of BSA, within 5Å distance.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135292.g003: Visualization of binding site of chaperones (A, B, C, D, E, F, G and H) into IIA and IIIA regions of BSA, within 5Å distance.
Mentions: The conformer with the lowest binding energy was calculated from 10 different conformations for each docking simulation, at 5 Å distance between chaperones and BSA (S1 Table). Finally, it was found that the chaperone-BSA binding site was located into the domain IIA and IIIA of the protein, which corresponds to the lowest free energy values calculated. According to the analysis of the calculated free energy, the binding process of BSA with chaperones is spontaneous (ΔG<0). The common amino acid residues lining this binding site were: His145, Glu186, Leu189, Thr190, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Ile455, Arg458 and Asp107, Ser109, Leu189, Thr190, Ala193, Arg196, Glu424, Ser428 Lys431, Val432, Arg435, Tyr451, Ile455, Arg458, for the 1G and 2G groups respectively. The compounds of the 3G group interact with the following common amino acid residues: Asp108, Glu186, Leu189, Thr190, Ser192, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Leu454, Ile455, and Arg458. Similarly, the binding amino acid residues for C and curcumin (H) are Glu186, Leu189, Thr190, Ser192, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Ile455, and Arg458. In 85% of calculations, the interaction zone was comprised between amino acids 145 to 458, specifically with the residues His145, Glu186, Leu189, Thr190, Ser192, Ala193, Arg196, Glu424, Ser428, Lys431, Val432, Arg435, Tyr451, Ile455, and Arg458. In general, these molecules bind to the sites via hydrophobic and Van der Waals forces. In some cases, hydrogen-bonding interactions have been observed. (Fig 3).

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