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

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 NPM1_264-277 K₂₆₇R, with the single mutation Lys²⁶⁷/Arg, exhibits the greater ability to act as a promoter of the amyloid aggregation of NPM1_264-277, limiting its toxicity and rescuing cell viability in OCI-AML3 cells.