# Discovery of a Minimally Charged Cell-Penetrating Peptide

## TL;DR

Researchers found a new cell-penetrating peptide with low charge that efficiently delivers molecules into cells without causing toxicity.

## Contribution

A minimally charged cell-penetrating peptide, BCP16e, was developed with high efficiency and safety.

## Key findings

- BCP16e has a +2 charge and shows high cytosolic entry efficiency.
- It maintains proteolytic stability and a better safety profile than its parent molecule.
- High cationic charge is not essential for efficient cell translocation.

## 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.