Drug Development in Conformational Diseases: A Novel Family of Chemical Chaperones that Bind and Stabilise Several Polymorphic Amyloid Structures.
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.
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.
Marquiza
M
Sablón-Carrazana
Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México; Departamento de Microbiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, México D.F., México.
Isaac
I
Fernández
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.
Alberto
A
Bencomo
Laboratorio de Nanobiología Celular, Departamento de Biología Celular, Facultad de Ciencias, UNAM, México D.F., México.
Reyna
R
Lara-Martínez
Dpto. Neurodiagnóstico, Centro de Neurociencias de Cuba, Cubanacán, Playa, La Habana, Cuba.
Suchitil
S
Rivera-Marrero
Instituto de Fisiología Celular, UNAM, México D.F., México.
Guadalupe
G
Domínguez
Dpto. Neurodiagnóstico, Centro de Neurociencias de Cuba, Cubanacán, Playa, La Habana, Cuba.
Rafaela
R
Pérez-Perera
Laboratorio de Nanobiología Celular, Departamento de Biología Celular, Facultad de Ciencias, UNAM, México D.F., México.
Luis Felipe
LF
Jiménez-García
Servicio de Endocrinología, Instituto Nacional de Pediatría, SS, México D.F., México.
Nelly F
NF
Altamirano-Bustamante
Dpto. Neurodiagnóstico, Centro de Neurociencias de Cuba, Cubanacán, Playa, La Habana, Cuba.
Massiel
M
Diaz-Delgado
Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
Fernand
F
Vedrenne
Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
Lina
L
Rivillas-Acevedo
Servicio de Endocrinología, Instituto Nacional de Pediatría, SS, México D.F., México; Cátedra Conacyt, México D.F., México.
Karina
K
Pasten-Hidalgo
Laboratorio de Nanobiología Celular, Departamento de Biología Celular, Facultad de Ciencias, UNAM, México D.F., México.
María de Lourdes
Mde L
Segura-Valdez
Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
Sergio
S
Islas-Andrade
Servicio de Endocrinología, Hospital de Pediatría, CMNXXI, IMSS, México D. F., México.
Eulalia
E
Garrido-Magaña
Centro de Investigaciones Clínicas, La Habana, Cuba.
Alejandro
A
Perera-Pintado
Centro de Investigaciones Clínicas, La Habana, Cuba.
Anaís
A
Prats-Capote
Dpto. Neurodiagnóstico, Centro de Neurociencias de Cuba, Cubanacán, Playa, La Habana, Cuba.
Chryslaine
C
Rodríguez-Tanty
Unidad de Investigación Médica en Enfermedades Metabólicas, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
Myriam M
MM
Altamirano-Bustamante
D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000378:metabolism; D058227:Amyloidogenic Proteins / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D002942:Circular Dichroism; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D006801:Humans; D066298:In Vitro Techniques; D046529:Microscopy, Electron, Transmission; D018832:Molecular Chaperones / Q000378:metabolism* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000187:drug effects / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000188:drug therapy; D012709:Serum Albumin / Q000378:metabolism / Q000494:pharmacology; D012710:Serum Albumin, Bovine / Q000378:metabolism / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D058227:Amyloidogenic Proteins; D018832:Molecular Chaperones; D010446:Peptide Fragments; D012709:Serum Albumin; C086839:amyloid beta-protein (17-42); D012710:Serum Albumin, Bovine