Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 54, Issue 3, Pages 858-868Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm101327d
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- Lytix Biopharma A/S
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We have prepared a series of highly potent achiral cationic beta(2,2)-amino acid derivatives that fulfill the Lipinski's rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest beta(2,2)-amino acid derivatives (M-w 423.6) exhibiting a MIC of 3.8 mu M against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 mu M against Escherichia coli. The beta(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the beta(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.
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