Combinatorial approach to lead optimization of a novel hexapeptide with antifungal activity.

Three sets of sublibraries of an antifungal lead peptide His-D-Trp-D-Phe-Phe-D-Phe-Lys-NH2 (I) have been prepared by introducing variations at positions 1, 4 and 6. They were screened for their antifungal activity against C. albicans and C. neoformans in order to quantify inhibition at each step of the hexapeptide sublibrary iteration. The studies led to the identification of Arg-D-Trp-D-Phe-Ile-D-Phe-His-NH2 as a novel hexapeptide with potent antifungal activity against both C. albicans and C. neoformans.