Identification of novel antifungal nonapeptides through the screening of combinatorial peptide libraries based on a hexapeptide motif.
Four sets of mixture based nonapeptide libraries derived from an antifungal hexapeptide pharmacophore Arg-D-Trp-D-Phe-Ile-D-Phe-His-NH(2) (II) have been synthesized. The three C-terminal positions 7, 8 and 9 were subject to randomization using 19 genetically coded amino acids. They were then screened for their antifungal activity against Candida albicans and Cryptococcus neoformans in order to quantify inhibition at each step of the nonapeptide sublibrary deconvolution. The studies led to the identification of several novel nonapeptides with potent antifungal activity. Two of the nonapeptides exhibited approximately 17-fold increase in the activity in comparison to the lead hexapeptide motif His-D-Trp-D-Phe-Phe-D-Phe-Lys-NH(2) (I) against C. albicans.
Kundu
B
B
Department of Medicinal Chemistry, Central Drug Research Institute, Lucknow-226 001, India. bijoy_kundu@yahoo.com
Srinivasan
T
T
Kesarwani
A P
AP
Kavishwar
A
A
Raghuwanshi
S K
SK
Batra
S
S
Shukla
P K
PK
D020816:Amino Acid Motifs; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects; D020650:Combinatorial Chemistry Techniques; D003455:Cryptococcus neoformans / Q000187:drug effects; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D019151:Peptide Library; D020539:Sequence Analysis, Protein / Q000379:methods; D013329:Structure-Activity Relationship
D000935:Antifungal Agents; D009842:Oligopeptides; D019151:Peptide Library