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-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 omega-aminoalkanoyl moiety having an optimal 11-carbon chain for inhibition (11-aminoundecanoyl-SKL-NH2, 3a, IC50 = 1.2 +/- 0.14 microM). 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 microM). Removal of the carboxamide moiety led to a metabolically stable dipeptide inhibitor containing an N-(cyclohexylethyl)lysinamide (17e, IC50 = 0.11 +/- 0.03 microM). Partial rigidification of the flexible aminoundecanoyl chain produced the dipeptide p-(omega-aminohexyl)phenacetyl-L-seryl-L-lysyl-N-(cyclohexyleth yl)amide (26b, IC50 = 0.11 +/- 0.04 microM). Subsequent incorporation of an alpha-methyl substituent into 26b provided the dipeptide analog [2-[p-(omega-aminohexyl)phenyl]propionyl]-L-seryl-L-lysyl-N-(cyclohex ylethyl)amide, a very potent inhibitor (48, IC50 = 0.043 +/- 0.006 microM), which retained the three essential elements required for recognition by the acyl transferase's peptide binding site.
Nagarajan
S R
SR
G. D. Searle Research and Development, c/o Monsanto Company, St. Louis, Missouri 63198, USA.
Devadas
B
B
Zupec
M E
ME
Freeman
S K
SK
Brown
D L
DL
Lu
H F
HF
Mehta
P P
PP
Kishore
N S
NS
McWherter
C A
CA
Getman
D P
DP
Gordon
J I
JI
Sikorski
J A
JA
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D002176:Candida albicans / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000577:Amides; D004791:Enzyme Inhibitors; D000217:Acyltransferases; C050480:glycylpeptide N-tetradecanoyltransferase