Antifungal peptides with novel specific inhibitors of glucosamine 6-phosphate synthase.
N3-4-Methoxyfumaroyl-L-2,3-diaminopropanoic acid (FMDP) has been found to be a strong and selective inhibitor of glucosamine 6-phosphate synthase from Candida albicans. Incorporation of FMDP into a dipeptide structure has produced effective antifungal agents (portage transport). A number of dipeptides containing FMDP have been synthesized, with Nva-FMDP showing the highest in vitro activity against different fungi, including Candida albicans (MIC90 = 2.2 micrograms/ml for 50 clinical strains), Cryptococcus neoformans and Aspergillus spp. This compound, when tested in a general candidiosis model infection in mice, gave PD50/10 and CD50/10 values of 5.0 and 1.63 mg/kg, respectively. Meanwhile, the LD50 value after i.v. administration was higher than 300 mg/kg.
Milewski
S
S
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, Poland.
Chmara
H
H
Andruszkiewicz
R
R
Borowski
E
E
Zaremba
M
M
Borowski
J
J
D000409:Alanine / Q000031:analogs & derivatives*; D000935:Antifungal Agents / Q000138:chemical synthesis*; D002175:Candida / Q000187:drug effects / Q000302:isolation & purification; D004151:Dipeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D005650:Fumarates / Q000138:chemical synthesis / Q000494:pharmacology*; D005658:Fungi / Q000187:drug effects; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing) / Q000037:antagonists & inhibitors*; D006801:Humans; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D000637:Transaminases / Q000037:antagonists & inhibitors*; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology
D000935:Antifungal Agents; D004151:Dipeptides; D005650:Fumarates; D015091:beta-Alanine; C056276:N(3)-(4-methoxyfumaroyl)-2,3-diaminopropionic acid; D000637:Transaminases; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D000409:Alanine