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 the N-terminal glycine residues of a variety of cellular proteins. Genetic studies have shown that NMT is essential for the viability of the principal fungal pathogens which cause systemic infection in immunosuppressed humans and hence is a target for development of fungicidal drugs, We have generated a class of potent peptidomimetic inhibitors of the NEAT from one such fungal pathogen, Candida albicans. The N-terminal tetrapeptide from a substrate analog inhibitor, ALYASKL-NH2, was replaced with an omega-aminoalkanoyl moiety having an optimal 11-carbon chain 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 dipeptide inhibitor containing an N-(cyclohexylethyl)lysinamide (17e, IC50 0.11+/-0.93 mu M). Partial rigidification of the flexible aminoundecanoyl chain produced the dipeptide p-(omega-aminohexyl)phenacetyl-L-seryl-L (cyclohexylethyl)amide (26b, IC50=0.11+/-0.04 mu M), Subsequent incorporation of an alpha-methyl substituent into 26b provided the dipeptide analog [2-[p-(omega-aminohexyl)phenyl]propionyl]-L-seryl-L-lysyl-N-(cyclohexylethyl)amide, a very potent inhibitor (48 IC50=0.043+/-0.006 mu M), which retained the three essential elements required for recognition by the acyl transferase's peptide binding site.