Bleomycin modulates amyloid aggregation in β-amyloid and hIAPP.

Area of Science:

• Biochemistry
• Neuroscience
• Endocrinology

Background:

• Aberrant protein misfolding and amyloid aggregation are hallmarks of neurodegenerative diseases like Alzheimer's and type 2 diabetes.
• Current inhibitors target specific amyloid peptides, posing challenges for broad-spectrum efficacy.
• Bleomycin (BLM), an established antibiotic and antitumor agent, has potential for novel therapeutic applications.

Purpose of the Study:

• To investigate the dual inhibitory effects of Bleomycin (BLM) on amyloid-beta (Aβ) and human islet amyloid polypeptide (hIAPP) aggregation.
• To explore BLM's potential as a broad-spectrum inhibitor against amyloid aggregation.

Main Methods:

• Utilized computational techniques, including replica exchange molecular dynamics simulations and drug repurposing.
• Employed experimental validation through in vitro amyloid aggregation assays.

Main Results:

• BLM binds to the critical β-sheet regions of both Aβ and hIAPP, destabilizing these structures.
• BLM significantly reduced the fibrillar load of Aβ and hIAPP in vitro.
• Demonstrated BLM's dual inhibitory activity against Aβ and hIAPP aggregation for the first time.

Conclusions:

• Bleomycin exhibits dual inhibitory effects on Aβ and hIAPP amyloid aggregation.
• BLM's mechanism involves binding and destabilizing key β-sheet structures.
• Further development of BLM could lead to novel, sequence-independent inhibitors for various amyloidogenic diseases.