This research project was begun this year with the object of preparing new inhibitors of the enzyme myristoyl-CoA: protein N-myristoyltransferase (NMT). This enzyme catalyzes the covalent modification of specific proteins by acylation of the N-terminal amino group with myristoyl-CoA. Biomedically important proteins which are myristoylated include oncoproteins such as p60src and the gag polyproteins of a number of retroviruses including HIV. Interference with myristoylation has been shown to greatly reduce the transforming potential of p60src without affecting its tyrosine kinase activity. Blocking of the myristoylation of the HIV gag protein by site-directed mutagenesis (N terminal glycine alanine) prevents viral particle release. Thus, potent chemical inhibitors of NMT should be useful for studies of the biochemical function(s) of protein myristoylation, and could potentially have therapeutic significance. A group of target structures have been identified as potential transition state or combined product inhibitors of NMT. Both irreversible and competitive inhibitors are sought. Synthesis, purification and characterization has been completed for 12 new compounds. These are being tested for inhibition of NMT both in vitro and with cells in tissue culture.
