Structure-activity relationships in peptide modulators of β-amyloid protein aggregation: variation in α,α-disubstitution results in altered aggregate size and morphology.
Neuronal cytotoxicity observed in Alzheimer's disease (AD) is linked to the aggregation of β-amyloid peptide (Aβ) into toxic forms. Increasing evidence points to oligomeric materials as the neurotoxic species, not Aβ fibrils; disruption or inhibition of Aβ self-assembly into oligomeric or fibrillar forms remains a viable therapeutic strategy to reduce Aβ neurotoxicity. We describe the synthesis and characterization of amyloid aggregation mitigating peptides (AAMPs) whose structure is based on the Aβ "hydrophobic core" Aβ(17-20), with α,α-disubstituted amino acids (ααAAs) added into this core as potential disrupting agents of fibril self-assembly. The number, positional distribution, and side-chain functionality of ααAAs incorporated into the AAMP sequence were found to influence the resultant aggregate morphology as indicated by ex situ experiments using atomic force microscopy (AFM) and transmission electron microscopy (TEM). For instance, AAMP-5, incorporating a sterically hindered ααAA with a diisobutyl side chain in the core sequence, disrupted Aβ(1-40) fibril formation. However, AAMP-6, with a less sterically hindered ααAA with a dipropyl side chain, altered fibril morphology, producing shorter and larger sized fibrils (compared with those of Aβ(1-40)). Remarkably, ααAA-AAMPs caused disassembly of existing Aβ fibrils to produce either spherical aggregates or protofibrillar structures, suggesting the existence of equilibrium between fibrils and prefibrillar structures.
Department of Chemistry, Louisana State University, Baton Rouge, Louisiana 70803, USA.
Cyrus K
CK
Bett
Johnpeter N
JN
Ngunjiri
Wilson K
WK
Serem
Krystal R
KR
Fontenot
Robert P
RP
Hammer
Robin L
RL
McCarley
Jayne C
JC
Garno
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D057927:Hydrophobic and Hydrophilic Interactions; D018625:Microscopy, Atomic Force / Q000379:methods; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C078592:amyloid beta-protein (1-40)