The goal of this project is the synthesis of new inhibitors of the enzyme myristoyl-CoA:protein N-myristoyltransferase (NMT).This enzyme catalyzes the covalent modification of specific proteins by acylating the amino group of N-terminal glycines with myristoyl-CoA. Biomedically important proteins which are myristoylated include oncoproteins such as p6O src and the gag polypeptide of HIV and other retroviruses. Other myristoylated proteins include inhibitory G-protein subunits, cyclic AMP- dependent protein kinase and calcineurin. Candidate inhibitors of NMT are analogs of the substrate intermediates or products of the NMT-catalyzed reactionare synthesized. Syntheses have been designed and carried out for over 20 initial target structures. These compounds fall into four general categories: truncated forms of myristoyl-CoA, non-hydrolyzable analogs of myristoyl-CoA, myristoylated-peptide product analogs, and peptide/CoA combined-product hybrids.
