Identification of Inhibitors of CD36-Amyloid Beta Binding as Potential Agents for Alzheimer's Disease.
Neuroinflammation is one of the hallmarks of Alzheimer's disease pathology. Amyloid β has a central role in microglia activation and the subsequent secretion of inflammatory mediators that are associated with neuronal toxicity. The recognition of amyloid β by microglia depends on the expression of several receptors implicated in the clearance of amyloid and in cell activation. CD36 receptor expressed on microglia interacts with fibrils of amyloid inducing the release of proinflammatory cytokines and amyloid internalization. The interruption of the interaction CD36-amyloid β compromises the activation of microglia cells. We have developed and validated a new colorimetric assay to identify potential inhibitors of the binding of amyloid β to CD36. We have found seven molecules, structural analogues of the Trichodermamide family of natural products that interfere with the interaction CD36-amyloid β. By combining molecular docking and dynamics simulations, we suggested the second fatty acids binding site within the large luminal hydrophobic tunnel, present in the extracellular domain of CD36, as the binding pocket of these compounds. Free energy calculations predicted the nonpolar component as the driving force for the binding of these inhibitors. These molecules also inhibited the production of TNF-α, IL-6, and IL-1β by peritoneal macrophages stimulated with fibrils of amyloid β. This work serves as a platform for the identification of new potential anti-inflammatory agents for the treatment of Alzheimer's disease.
Centro de Biología Molecular y Celular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge #219, Panama City, 0843-01103 Panama.|Department of Biotechnology, Acharya Nagarjuna University , Nagarjuna Nagar, Guntur, Andhra Pradesh 522510, India.
Deborah
D
Doens
Centro de Estudios de Proteínas, Facultad de Biología, Universidad de La Habana , La Habana, Cuba.
Pedro A
PA
Valiente
Adelphe M
AM
Mfuh
Anh
A
X T Vo
Centro de Biología Molecular y Celular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge #219, Panama City, 0843-01103 Panama.
Adilia
A
Tristan
Centro de Biología Molecular y Celular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge #219, Panama City, 0843-01103 Panama.
Lizmar
L
Carreño
Centro de Biología Molecular y Celular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge #219, Panama City, 0843-01103 Panama.
Mario
M
Quijada
Vu T
VT
Nguyen
George
G
Perry
Oleg V
0000-0002-3026-1135
OV
Larionov
Centro de Biología Molecular y Celular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge #219, Panama City, 0843-01103 Panama.
Ricardo
R
Lleonart
Centro de Biología Molecular y Celular de Enfermedades, Instituto de Investigaciones Científicas y Servicios de Alta Tecnología (INDICASAT-AIP) , City of Knowledge #219, Panama City, 0843-01103 Panama.
Patricia L
PL
Fernández
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000187:drug effects*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology; D018955:CD36 Antigens / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D051379:Mice; D017628:Microglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects
D016229:Amyloid beta-Peptides; D000893:Anti-Inflammatory Agents; D018955:CD36 Antigens; D018696:Neuroprotective Agents
Alzheimer’s disease; CD36; amyloid β; inflammation; microglia; trichodermamide