A superactive peptidomimetic analog of a farnesylated dodecapeptide yeast pheromone

The S. cerevisiae a-factor, YIIKGVFWDPAC(s-farnesyl)-OCH3, is one of two peptide mating pheromones which mediate cell-cell communication in S. cerevisiae. We previously reported that replacing Gly5 with D-Ala led to a 4-6 fold increase in activity while the L-Ala5 homolog was 4 to 16-fold less active than the wildtype. To clarify the structural implications of these findings, we conformationally restricted the center of the pheromone by inserting gamma-lactam constraints in place of either the Lys4Gly5 or the Gly5Val6 dipeptide unit. Incorporation of (R)-3-amino-2-oxo-1-pyrrolidineacetic acid in place of Lys4Gly5 led to a super-active agonist which exhibited a 32-fold higher bioactivity than that of the a-factor. In contrast, an analog with (S)-3-amino-2-oxo-1-pyrrolidineacetic acid in place of Gly5Val6 is about 30 to 60-fold less active than the a-factor. These data strongly suggest that the a-factor adopts a reverse turn as its bioactive conformation.