DIFFERENTIAL INHIBITION OF FUNGAL AND MAMMALIAN SQUALENE EPOXIDASES BY THE BENZYLAMINE SDZ-SBA-586 IN COMPARISON WITH THE ALLYLAMINE TERBINAFINE

The allylamine class of antifungal compounds are specific inhibitors o f squalene epoxidase (SE). However, depending on their chemical struct ure, allylamine derivatives can be highly selective for either fungal or mammalian SEs. All allylamines tested previously, irrespective of t heir selectivity, inhibit fungal SEs in a noncompetitive manner and ma mmalian SEs in a competitive manner. Here we have analyzed the inhibit ory properties of the benzylamine SDZ SBA 586 toward fungal and mammal ian SEs in comparison to the systemic antimycotic terbinafine. SDZ SBA 586 was, like terbinafine, a selective inhibitor of fungal SE. Micros omal SE from the pathogenic yeast Candida albicans was sixfoId more se nsitive to SDZ SBA 586 than to terbinafine, IC50: 8 nM versus 44 nM, w hile the enzyme from the dermatophyte fungus Trichophyton rubrum was s lightly less sensitive to SDZ SBA 586 than to terbinafine, IC50: 39 an d 18 nM, respectively. Similarly to terbinafine, SDZ SBA 586 inhibited the yeast enzyme in a noncompetitive manner. SDZ SBA 586 also inhibit ed mammalian microsomal SEs, but only at micromolar concentrations. It was more active than terbinafine toward both guinea pig SE, IC50: 2 E LM versus 4 mu M, and rat SE, IC50: 11 mu M versus 87 mu M. However, i n contrast to terbinafine as well as allylamines selective for mammali an SE, SDZ SBA 586 was a noncompetitive inhibitor of rat microsomal SE . Interestingly, depending on the source of microsomal SE, binding of terbinafine and SDZ SBA 586 exhibited a positive, indifferent, or nega tive cooperativity, suggesting that SE is an oligomeric enzyme. (C) 19 97 Academic Press.