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Novel Biologically Active Nonpeptidic Inhibitors of MyristoylCoA:Protein N -Myristoyltransferase

1998; American Chemical Society; Volume: 41; Issue: 6 Linguagem: Inglês

10.1021/jm980001q

1520-4804

Balekudru Devadas, Sandra K. Freeman, Charles A. McWherter, Nandini S. Kishore, Jennifer K. Lodge, Emily Jackson-Machelski, Jeffrey I. Gordon, James A. Sikorski,

Biochemical and Molecular Research

A new class of biologically active nonpeptidic inhibitors of Candida albicans NMT has been synthesized starting from the octapeptide ALYASKLS-NH2 (2). The synthetic strategy entailed the preparation of novel protected Ser-Lys mimics 9 and 12 from (S)- or (R)-3-iodotyrosine and then grafting key enzyme recognition elements in a stepwise manner. Like 2, compounds 16, 17, and 18 are competitive Candida NMT inhibitors that bind to the peptide recognition site of the enzyme. Moreover, 16−18 have an affinity comparable to that of 2 even though they are devoid of peptide bonds. In contrast to 2, these nonpeptidic inhibitors exhibit antifungal activity.