Lipidated peptides and the limits of chemical control

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Abstract
Peptide lipidation is widely employed to enhance the apparent biological performance of peptide-based systems by improving stability, membrane association, and systemic persistence. However, increased potency is often interpreted uncritically as evidence of improved molecular design. This Perspective highlights that lipidation can reshape peptide behaviour by partially shifting functional control from sequence-encoded molecular recognition toward context-dependent effects in which membrane interactions, carrier binding, supramolecular assembly, and residence time play an increasingly important role. Under such design-dependent conditions, enhanced activity may primarily reflect delivery- and exposure-driven amplification rather than improved intrinsic efficacy. While MIC values and endpoint assays remain valuable benchmarks of activity, they are insufficient on their own to guide rational optimization of lipidated peptides, as they conflate intrinsic activity with lipid-driven distribution and time-dependent effects. Accordingly, this Perspective argues not against lipidation itself, but for reframing lipidation as a deliberately controllable interaction element rather than a generic potency modifier, thereby restoring mechanistic interpretability and design robustness in peptide chemical biology.

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