Activation of the 20S proteasome as a possible strategy to counteract amylin oligomerization in type 2 diabetes.

IF 4.5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Bioorganic Chemistry Pub Date : 2025-01-10 DOI:10.1016/j.bioorg.2025.108157

Daria Sowik, Małgorzata Giżyńska, Karolina Trepczyk, Julia Witkowska, Elżbieta Jankowska

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Abstract

Human amylin, called also islet amyloid polypeptide (hIAPP), is the principal constituent of amyloid deposits in the pancreatic islets. Together with hyperglycemia, hIAPP-derived oligomers and aggregates are important culprits in type 2 diabetes mellitus (T2DM). Preventing aggregation, and in particular inhibiting the formation and/or stimulating degradation of toxic amylin oligomers formed early in the process, may reduce the negative effects of T2DM. Such therapeutic intervention may be enabled by activation of the 20S proteasome, a proteolytic system responsible for digesting proteins that are damaged or natively exhibit aggregation tendencies. In this work, we showed that in the lag phase of the aggregation process, soluble oligomers of small size (dimer to heptamer) were present alongside the amylin monomer. These oligomers inhibited the activity of the human 20S proteasome (h20S). To counteract this inhibition, we designed two activators that proved to be effective in restoring the peptidase efficiency of h20S to basal levels and even stimulating the enzyme to degrade the fluorogenic substrate more efficiently. They showed this effect both against isolated h20S and in cell lysate.

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来源期刊

Bioorganic Chemistry 生物-生化与分子生物学

CiteScore

9.70

自引率

3.90%

发文量

679

审稿时长

31 days

期刊介绍： Bioorganic Chemistry publishes research that addresses biological questions at the molecular level, using organic chemistry and principles of physical organic chemistry. The scope of the journal covers a range of topics at the organic chemistry-biology interface, including: enzyme catalysis, biotransformation and enzyme inhibition; nucleic acids chemistry; medicinal chemistry; natural product chemistry, natural product synthesis and natural product biosynthesis; antimicrobial agents; lipid and peptide chemistry; biophysical chemistry; biological probes; bio-orthogonal chemistry and biomimetic chemistry. For manuscripts dealing with synthetic bioactive compounds, the Journal requires that the molecular target of the compounds described must be known, and must be demonstrated experimentally in the manuscript. For studies involving natural products, if the molecular target is unknown, some data beyond simple cell-based toxicity studies to provide insight into the mechanism of action is required. Studies supported by molecular docking are welcome, but must be supported by experimental data. The Journal does not consider manuscripts that are purely theoretical or computational in nature. The Journal publishes regular articles, short communications and reviews. Reviews are normally invited by Editors or Editorial Board members. Authors of unsolicited reviews should first contact an Editor or Editorial Board member to determine whether the proposed article is within the scope of the Journal.