Targeting Protein Phosphorylation with Molecularly Imprinted Polymer Receptors

Protein phosphorylation is a reversible post-translational modification (PTM) acting as a key regulator of protein function with an impact on cell behavior and pathological conditions. Accurate monitoring of protein phosphorylation status is important for both mechanistic deciphering of cellular processes and disease diagnostics. However, detecting this PTM remains challenging due to its transient nature, stability issues, and low abundance. Molecularly imprinted polymers (MIPs) fill a void in the search for robust affinity techniques that can be tailored to specifically enrich phospho-peptides at predetermined levels of discrimination. This ranges from (i) surface-imprinted mesoporous materials for generic enrichment; (ii) amino acid–specific receptors that fractionate by side chain with minimal sequence bias; (iii) dummy-templated MIPs for labile phosphorylations; to (iv) sequence-specific receptors for defined phospho-epitopes and biomarkers. This review offers a concise, interdisciplinary overview of the field in the context of current challenges in phosphoproteomics. • MIPs combine antibody-like selectivity with metal-oxide robustness for use in phosphopeptide enrichment. • Phospho-specific MIPs can target residues, labile PTMs, or defined sequence motifs. • MIPs enrich distinct phosphopeptide isoforms even from highly complex proteomes.