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-NH2 (11) 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, (1) against C. albicans. (C) 2002 Elsevier Science Ltd. All rights reserved.