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"The pharmaceutical industry is constantly searching for new drugs, but can existing drugs be rendered more effective? More than half of the drugs we use are, in terms of their chemical properties, weakly basic. In a new study ... showed that this property may reduce the drugs’ effectiveness: Their availability in the cell is decreased by their tendency to bind to large, charged molecules within the cell or to become trapped inside acidic organelles, such as the cellular recycling bin called the lysosome. The result is decreased activity, which leads to the use of larger doses that can aggravate side effects and cause unwanted interactions with other drugs.
The researchers then showed that this problem can be overcome by a chemical modification – addition of an acetyl group – that makes these drugs more available for activity in the cell. These findings highlight the importance of taking intra-cellular dynamics into account in the course of drug development. They may help improve the effectiveness of a wide range of drugs, making it possible to reduce their dosage, thereby decreasing side effects."
"eLife Assessment
This is a valuable study on the diffusion rates of drug molecules in human-derived cells, presenting convincing data indicating that their diffusion behavior depends on their charged state. It proposes that blocking drug protonation enhances diffusion and fractional recovery, suggesting improved intracellular availability of weakly basic drugs. The findings are significant for drug design and understanding the biophysical behavior of small molecules in cells."
From the abstract:
"For drugs to be active they have to reach their targets. Within cells this requires crossing the cell membrane, and then free diffusion, distribution, and availability. Here, we explored the in-cell diffusion rates and distribution of a series of small molecular fluorescent drugs, in comparison to proteins, by microscopy and fluorescence recovery after photobleaching (FRAP). While all proteins diffused freely, we found a strong correlation between pKa and the intracellular diffusion and distribution of small molecule drugs.
Weakly basic, small-molecule drugs displayed lower fractional recovery after photobleaching and 10- to-20-fold slower diffusion rates in cells than in aqueous solutions. As, more than half of pharmaceutical drugs are weakly basic, they, are protonated in the cell cytoplasm. Protonation, facilitates the formation of membrane impermeable ionic form of the weak base small molecules. This results in ion trapping, further reducing diffusion rates of weakly basic small molecule drugs under macromolecular crowding conditions where other nonspecific interactions become more relevant and dominant. Our imaging studies showed that acidic organelles, particularly the lysosome, captured these molecules. Surprisingly, blocking lysosomal import only slightly increased diffusion rates and fractional recovery. Conversely, blocking protonation by N-acetylated analogues, greatly enhanced their diffusion and fractional recovery after FRAP. Based on these results, N-acetylation of small molecule drugs may improve the intracellular availability and distribution of weakly basic, small molecule drugs within cells."
Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration (open access)
Fig. 3 Fluorescein, CCF2 and CF514 diffusion in PBS and inside HeLa cells.
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