ArticleChembiochem : a European journal of chemical biology2025
PCFT-Independent Cellular Uptake of Cyclic Cell-Penetrating Peptide-Conjugated Folic Acid.
Article in Chembiochem : a European journal of chemical biology, 2025. 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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Abstract
Folic acid is an essential component of many metabolic processes, including the synthesis of nucleoproteins, purines, and pyrimidines, and is a recommended supplement to lower the incidence of various disorders. Folic acid and folate-loaded nanoparticles are extensively evaluated for sustained release and enhanced stability of the molecule; however, malfunctioning of proton-coupled folate transporters (PCFTs) present on the intestinal cells and subsequent folate deficiency remain a major issue in this context. This study provides the first demonstration where cell-penetrating peptide-conjugated folic acid mediates PCFT-independent folic acid permeabilization and intracellular bioavailability in vitro in the intestinal cells and macrophages. Cyclic-transactivating transcriptional activator (cTAT) folic acid conjugates are prepared by solid-phase peptide synthesis and are evaluated for the cellular uptake and bioavailability in the presence and absence of PCFT inhibitors. Compared with free folic acid that showed PCFT-mediated cellular uptake, cTAT-folic acid conjugates exhibited enhanced cellular uptake at all studied pH and improved intracellular bioavailability of the cargo, as was determined by dihydrofolate reductase (DHFR) assay. Folic acid and cTAT-folic acid conjugates also dampened the production of proinflammatory mediators in the presence of toxins in vitro in macrophage cell lines.
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