Insight Into the Kinetic of Amyloid β (1–42) Peptide Self‐Aggregation: Elucidation of Inhibitors’ Mechanism of Action
Tóm tắt
The initial transition of amyloid β (1–42) (Aβ42) soluble monomers/small oligomers from unordered/α‐helix to a β‐sheet‐rich conformation represents a suitable target to design new potent inhibitors and to obtain effective therapeutics for Alzheimer's disease. Under optimized conditions, this reliable and reproducible CD kinetic study showed a three‐step sigmoid profile that was characterized by a lag phase (prevailing unordered/α‐helix conformation), an exponential growth phase (increasing β‐sheet secondary structure) and a plateau phase (prevailing β‐sheet secondary structure). This kinetic analysis brought insight into the inhibitors' mechanism of action. In fact, an increase in the duration of the lag phase can be related to the formation of an inhibitor–Aβ complex, in which the non‐amyloidogenic conformation is stabilized. When the exponential rate is affected exclusively, such as in the case of Congo red and tetracycline, then the inhibitor affinity might be higher for the pleated β‐sheet structure. Finally, by adding the inhibitor at the end of the exponential phase, the soluble protofibrils can be disrupted and the Aβ amyloidogenic structure can revert into monomers/small oligomers. Congo red and tetracycline preferentially bind to amyloid in the β‐sheet conformation because both decreased the slope of the exponential growth, even if to a different extent, whereas no effect was observed for tacrine and galantamine. Some very preliminary indications can be derived about the structural requirements for binding to nonamyloidogenic or β‐sheet amyloid secondary structure for the development of potent antiaggregating agents. On these premises, memoquin, a multifunctional molecule that was designed to become a drug candidate for the treatment of Alzheimer's disease, was investigated under the reported circular dichroism assay and its anti‐amyloidogenic mechanism of action was elucidated.
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Tài liệu tham khảo
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