Peptidomimetics Targeting the Amyloidogenicity of Nucleophosmin 1 Mutations in Acute Myeloid Leukemia

TL;DR

This paper explores how engineered peptides can enhance amyloid aggregation in mutated NPM1 proteins linked to AML, potentially reducing toxicity and improving cell survival.

Contribution

The study introduces novel peptides designed to modulate amyloid aggregation in mutated NPM1, offering a new therapeutic strategy for AML.

Findings

Peptides with conservative mutations in NPM1264-277 enhance amyloid aggregation propensity.

The K267R mutation in NPM1264-277 reduces toxicity and rescues cell viability in OCI-AML3 cells.

Biophysical assays confirm structural and functional changes in modified peptides.

Abstract

Nucleophosmin 1(NPM1) is an abundant human protein endowed with many functions where whose dysregulation leads to various cancers and mutations are relevant in acute myeloid leukemia (AML). In the wild‐type form, pentameric NPM1 resides mainly in the nucleolus even if it shuttles toward the cytosol exerting its chaperon function; conversely in AML‐mutated versions, it has mainly a cytoplasmic localization, hence the name NPMc+. All types of AML mutations determine an important amyloid aggregation propensity of the C‐terminal domains (CTD) of NPMc+ and to exploit this amyloidogenicity for therapeutical purposes; herein, this study presents the design and structural and functional investigations of a series of peptides analogs of the sequence of the second helix of the three‐helix bundle of the wt CTD as potential enhancers of amyloid aggregation. Peptides are designed by introducing conservative mutations in the native 264−277 fragment, and their structural features and amyloid propensities are assessed through ThT fluorescence, circular dichroism spectroscopies and scanning electron microscopy. Several “accelerator sequences” are employed in amyloid seeding assays (ASAs): The sequence NPM1264‐277 K267R, with the single mutation Lys267/Arg, exhibits the greater ability to act as a promoter of the amyloid aggregation of NPM1264‐277, limiting its toxicity and rescuing cell viability in OCI‐AML3 cells.

Previous studies reveal an unexpected tendency for amyloid aggregation in specific regions of the C‐terminal domain (CTD) of nucleophosmin 1 (NPM1), a nucleolar chaperone involved in acute myeloid leukemia (AML). Herein, several peptide analogs of NPM1264‐277 (amyloid core) with conservative substitutions are designed and evaluated through biophysical and cellular assays as potential modulators of amyloid aggregation in AML.© 2025 WILEY‐VCH GmbH

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