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Abstract Rapid cellular uptake of synthetic molecules remains a challenge, and the motif frequently employed to generate prodrugs, succinic ester, unfortunately lowers the efficacy of the desired drugs due to their slow ester hydrolysis and low cell entry. Here we show that succinic ester‐containing diglycine drastically boosts the cellular uptake of supramolecular assemblies or prodrugs. Specifically, autohydrolysis of the diglycine‐activated succinic esters turns the nanofibers of the conjugates of succinic ester and self‐assembling motif into nanoparticles for fast cellular uptake. The autohydrolysis of diglycine‐activated succinic esters and drug conjugates also restores the efficacy of the drugs. 2D nuclear magnetic resonance (NMR) suggests that a “U‐turn” of diglycine favors intramolecular hydrolysis of diglycine‐activated succinic esters to promote autohydrolysis. As an example of rapid autohydrolysis of diglycine‐activated succinic esters for instant cellular uptake, this work illustrates a nonenzymatic bond cleavage approach to develop effective therapeutics for intracellular targeting.
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Autocleaving Bonds for Better Drugs
Abstract While bond formation has historically been the mainstay of medicinal chemistry, the phenomenon of bond cleavage has received less focus. However, the success of numerous oral medications demonstrates the importance of controlled cleavage in prodrugs to achieve desired therapeutic outcomes. Nevertheless, effective strategies to control this cleavage remain limited. This concept article introduces a novel approach: employing peptides as conjugates to drugs to modulate the hydrolysis of these conjugates and enhance drug efficacy. The article begins by briefly outlining common prodrug strategies, followed by a few representative examples of how peptides can be leveraged to control the autohydrolysis of peptide‐conjugated prodrugs for bacterial and cancer cell inhibition. Finally, it provides a brief outlook on the future potential of this promising new research direction in molecular medicine.
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- Award ID(s):
- 2011846
- PAR ID:
- 10520027
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- ChemMedChem
- Volume:
- 19
- Issue:
- 13
- ISSN:
- 1860-7179
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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