Conformationally constrained [p-(ω-aminoalkyl)phenacetyl]-L-seryl-L- lysyl dipeptide amides as potent peptidomimetic inhibitors of Candida albicans and human myristoyl-CoA:protein N-myristoyl transferase

Srinivasan R. Nagarajan, Balekudru Devadas, Mark E. Zupec, Sandra K. Freeman, David L. Brown, Hwang Fun Lu, Pramod P. Mehta, Nandini S. Kishore, Charles A. McWherter, Daniel P. Getman, Jeffrey I. Gordon, James A. Sikorski

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40 Scopus citations

Abstract

MyristoylCoA:protein N-myristoyltransferase (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 NMT from one such fungal pathogen, Candida albicans. The N-terminal tetrapeptide from a substrate analog inhibitor, ALYASKL-NH2, was replaced with an ω-aminoalkanoyl moiety having an optimal 11-carbon chain for inhibition (11-aminoundecanoyl-SKL-NH2, 3a, IC50 = 1.2 ± 0.14 μM). A series of replacements for the C-terminal Leu established that residues containing a lipophilic side chain were most effective, with cyclohexylalanine having the greatest potency (3g, IC50 = 0.36 ± 0.06 μM). Removal of the carboxamide moiety led to a metabolically stable dipeptide inhibitor containing an N(cyclohexylethyl)lysinamide (17e, IC50 = 0.11 ± 0.03 μM). Partial rigidification of the flexible aminoundecanoyl chain produced the dipeptide p-(ω-aminohexyl)phenacetyl-L- seryl-L-lysyl-N-(cyclohexylethyl)amide (26b, IC50 = 0.11 ± 0.04 μM). Subsequent incorporation of an α-methyl substituent into 26b provided the dipeptide analog [2-[p-(ω-aminohexyl)phenyl]propionyl]-L-seryl-L-lysyl-N- (cyclohexylethyl)amide, a very potent inhibitor (48, IC50 = 0.043 ± 0.006 μM), which retained the three essential elements required for recognition by the acyl transferase's peptide binding site.

Original languageEnglish
Pages (from-to)1422-1438
Number of pages17
JournalJournal of Medicinal Chemistry
Volume40
Issue number10
DOIs
StatePublished - May 9 1997

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