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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
10
|
| pubmed:dateCreated |
1997-6-6
|
| pubmed:abstractText |
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.
|
| pubmed:language |
eng
|
| pubmed:journal | |
| pubmed:citationSubset |
IM
|
| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
May
|
| pubmed:issn |
0022-2623
|
| pubmed:author |
pubmed-author:BrownD LDL,
pubmed-author:DevadasBB,
pubmed-author:FreemanS KSK,
pubmed-author:GetmanD PDP,
pubmed-author:GordonJ IJI,
pubmed-author:KishoreN SNS,
pubmed-author:MaH KHK,
pubmed-author:McWherterC ACA,
pubmed-author:MehtaP PPP,
pubmed-author:NagarajanS RSR,
pubmed-author:SikorskiJ AJA,
pubmed-author:ZupecM EME
|
| pubmed:issnType |
Print
|
| pubmed:day |
9
|
| pubmed:volume |
40
|
| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
|
| pubmed:pagination |
1422-38
|
| pubmed:dateRevised |
2006-11-15
|
| pubmed:meshHeading |
pubmed-meshheading:9154965-Acyltransferases,
pubmed-meshheading:9154965-Amides,
pubmed-meshheading:9154965-Candida albicans,
pubmed-meshheading:9154965-Enzyme Inhibitors,
pubmed-meshheading:9154965-Humans,
pubmed-meshheading:9154965-Magnetic Resonance Spectroscopy,
pubmed-meshheading:9154965-Molecular Conformation,
pubmed-meshheading:9154965-Spectrometry, Mass, Fast Atom Bombardment
|
| pubmed:year |
1997
|
| pubmed:articleTitle |
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.
|
| pubmed:affiliation |
G. D. Searle Research and Development, c/o Monsanto Company, St. Louis, Missouri 63198, USA.
|
| pubmed:publicationType |
Journal Article
|