Structure-activity relationships in the dodecapeptide .alpha.-factor of Saccharomyces cerevisiae: position 6 analogs are poor inducers of agglutinability

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Abstract
Des-Trp1,Cha3,X6 analogs (5) of .alpha.-factor, where X= Ala, Val, Ile, Nle or D-Leu and X = Leu in the natural .alpha.-factor sequence, were prepared by solution-phase techniques utilizing isobutyl chloroformate or 1-hydroxybenzotriazole accelerated active esters as the coupling agents. Purification to .gtoreq. 98% homogeneity was accomplished by high-performance liquid chromatography on a reversed-phase .mu.Bondapak C18 column with methanol/water/trifluoroacetic acid as the mobile phase. Three of the synthesized analogs (X6 = Val, Ile, Nle) induced morphogenesis and increased agglutinability in a cells. These substitutions demonstrate that a .gamma.-branched side chain at position 6 is not essential for biological activity. All of the active analogs induced morphogenesis at lower concentrations than they induced enhanced agglutinability. These results and other structure-activity relationships indicate that the agglutination and morphological repsonses to .alpha.-factor can be varied independently. Replacement of Leu6 with Ala or D-Leu resulted in inactive analogs that were not antagonistic for .alpha.-factor activity. Cell-mediated hydrolysis experiments indicated that the biological activities of the .alpha.-factor analogs are independent of their rates of degradation. All position 6 analogs were hydrolyzed more slowly than the parent compound, suggesting that the enzyme which degrades .alpha.-factor is highly specific for the native structure.