Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F24%3A00603171" target="_blank" >RIV/61388963:_____/24:00603171 - isvavai.cz</a>

Result on the web

<a href="https://doi.org/10.7554/eLife.97255.3" target="_blank" >https://doi.org/10.7554/eLife.97255.3</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.7554/eLife.97255" target="_blank" >10.7554/eLife.97255</a>

Result language

angličtina

Original language name

Reversing protonation of weakly basic drugs greatly enhances intracellular diffusion and decreases lysosomal sequestration

Original language description

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.

Czech name

—

Czech description

—

Type

J_SC - Article in a specialist periodical, which is included in the SCOPUS database

CEP classification

—

OECD FORD branch

10401 - Organic chemistry

Project

<a href="/en/project/GA22-20319S" target="_blank" >GA22-20319S: Photochemical Catch and Release Strategy: Towards Novel Molecular Switches and Bioorthogonal Reactions</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2024

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

eLife

ISSN

2050-084X

e-ISSN

2050-084X

Volume of the periodical

13

Issue of the periodical within the volume

December

Country of publishing house

GB - UNITED KINGDOM

Number of pages

24

Pages from-to

RP97255

UT code for WoS article

001524756300001

EID of the result in the Scopus database

2-s2.0-85211830620