CONFORMATIONALLY CONSTRAINED [P-(OMEGA-AMINOALKYL)PHENACETYL]-L-SERYL-L-LYSYL DIPEPTIDE AMIDES AS POTENT PEPTIDOMIMETIC INHIBITORS OF CANDIDA-ALBICANS AND HUMAN MYRISTOYL-COA-PROTEIN N-MYRISTOYL TRANSFERASE

MyristoylCoA:protein N-mylistoyltransferase (NMT) covalently attaches the 14-carbon saturated fatty acid myristate, via an amide bond, to th e N-terminal glycine residues of a variety of cellular proteins. Genet ic studies have shown that NMT is essential for the viability of the p rincipal fungal pathogens which cause systemic infection in immunosupp ressed humans and hence is a target for development of fungicidal drug s, We have generated a class of potent peptidomimetic inhibitors of th e NEAT from one such fungal pathogen, Candida albicans. The N-terminal tetrapeptide from a substrate analog inhibitor, ALYASKL-NH2, was repl aced with an omega-aminoalkanoyl moiety having an optimal 11-carbon ch ain for inhibition (11-aminoundecanoyl-SKL-NH2, 3a, IC50=1.2+/-0.14 mu M). A series of replacements for the C-terminal Leu established that residues containing a lipophiiic side chain were most effective, with cyclohexylalanine having the greatest potency (3g, IC50=0.36+/-0.06 mu M). Removal of the carboxamide moiety led to a metabolically stable d ipeptide inhibitor containing an N-(cyclohexylethyl)lysinamide (17e, I C50 0.11+/-0.93 mu M). Partial rigidification of the flexible aminound ecanoyl chain produced the dipeptide p-(omega-aminohexyl)phenacetyl-L- seryl-L (cyclohexylethyl)amide (26b, IC50=0.11+/-0.04 mu M), Subsequen t incorporation of an alpha-methyl substituent into 26b provided the d ipeptide analog opionyl]-L-seryl-L-lysyl-N-(cyclohexylethyl)amide, a v ery potent inhibitor (48 IC50=0.043+/-0.006 mu M), which retained the three essential elements required for recognition by the acyl transfer ase's peptide binding site.