ArticleBiochemistry2026
Discovery of a Minimally Charged Cell-Penetrating Peptide.
Article in Biochemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Authors and funding
4 authors.
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Abstract
Cell-penetrating peptides (CPPs) are powerful tools for delivering membrane-impermeable biomolecules into eukaryotic cells, with broad applications ranging from therapeutics to biopesticides. However, conventional linear CPPs typically require a high density of positive charges (at least +6) to function, often resulting in dose-limiting toxicity and off-target effects. Reducing this charge without sacrificing delivery efficiency remains a significant challenge. In this study, we performed a structure-activity relationship (SAR) analysis and medicinal chemistry optimization of the bismuth-mediated bicyclic CPP, BCP16. This campaign led to the discovery of BCP16e, a potent analog that carries only a +2 charge at physiological pH. Compared to its parent molecule, BCP16e exhibits significantly higher cytosolic entry efficiency, similar proteolytic stability, and a superior safety profile. Our findings demonstrate that high cationic charge is not a prerequisite for efficient translocation, providing a framework for the design of minimally charged, high-efficiency vehicles for intracellular delivery.
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