Drug Development in Conformational Diseases: A Novel Family of Chemical Chaperones that Bind and Stabilise Several
Marquiza Sablón-Carrazana1, Isaac Fernández2, Alberto Bencomo1
1Dpto. 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.
Insights
This study introduces a novel family of chemical chaperones (NCHCHF) to combat protein aggregation in conformational diseases like Alzheimer's and diabetes. These chaperones show potential in stabilizing or destabilizing protein structures to prevent toxic aggregation and protect cells.
Area of Science:
- Biochemistry and Molecular Biology
- Neuroscience
- Pharmacology
Background:
- Conformational diseases, including Alzheimer's disease, type 2 Diabetes Mellitus, and cancer, are increasing globally, causing significant suffering and economic burden.
- Protein aggregation is a key pathological mechanism in these diseases, necessitating novel therapeutic strategies.
- Existing treatments often focus on late-stage interventions, highlighting the need for approaches targeting various disease stages.
Purpose of the Study:
- To investigate the role of a novel family of chemical chaperones (NCHCHF) in preventing and managing protein aggregation in conformational diseases.
- To compare the interaction sites of NCHCHF with Bovine Serum Albumin (BSA), Human Islet Amyloid Polypeptide (hIAPP), and amyloid-beta fragments (Aβ17-42, Aβ16-21).
- To explore the potential of NCHCHF as therapeutic agents across different physiopathological stages of conformational diseases.
Main Methods:
- In silico and in vitro studies were employed to analyze the interactions between NCHCHF and various protein targets.
- Ligandability of Bovine Serum Albumin (BSA):NCHCHF was compared with interaction sites in Human Islet Amyloid Polypeptide (hIAPP):NCHCHF and amyloid pharmacophore fragments (Aβ17-42, Aβ16-21):NCHCHF.
- Cerebellar granule cells (CGC) were used to assess the protective effects of NCHCHF against cytotoxicity induced by hIAPP20-29 or low potassium medium.
Main Results:
- A meta-structure of pharmacophore was proposed, formed by merging interaction sites, enabling chaperones to prevent protein aggregation at various states.
- Specific NCHCHF were identified: Chaperone F accelerates fiber formation for acute cytotoxicity, while Chaperones A, B, C, and D stabilize native and fibril structures for chronic stages.
- All tested NCHCHF demonstrated the ability to protect and recondition cerebellar granule cells (CGC) from cytotoxicity, irrespective of their in vitro fiber formation kinetics.
Conclusions:
- The novel chemical chaperones family (NCHCHF) offers a versatile approach to target protein aggregation in conformational diseases.
- NCHCHF can be tailored to address specific physiopathological stages, from acute cytotoxicity to chronic disease management.
- Further in vivo animal experiments are warranted to validate the therapeutic potential of NCHCHF in cognitive and metabolic syndromes.
Related Concept Videos
03:03Amyloid Fibrils
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
03:03Amyloid Fibrils
03:00Molecular Chaperones and Protein Folding
The...
03:00Molecular Chaperones and Protein Folding
01:25Protein Folding
Protein Structure Is Critical to Its Biological Function
Proteins perform a wide range of biological functions such as catalyzing chemical reactions, providing...
01:22Protein Folding