W0409

Early-Stage Structural Studies Facilitate Discovery of Novel Bacterial Methionine Aminopeptidase Inhibitors. Artem G. Evdokimov(1), Matthew Pokross ¹, Richard L. Walter⁴, Marlene Mekel⁴, Bobby L. Barnett ¹, Jack Amburgey², William L. Seibel², Shari J. Soper², Jane Djung², Neil Fairweather², Conrad Diven ¹, Vinit Rastogi ¹, Leo Grinius², Charles Klanke², Richard Siehnel², Tracy Twinem³, and Alan Curnow², ¹Structural Biology, ²Anti-Infective Focus Area, and ³Protein Engineering Core Facility, The Procter & Gamble Company, 8700 Mason-Montgomery Rd., Mason, 45140 OH, ⁴Central Research Div., Miami Valley Laboratories, The Procter & Gamble Company.

Methionine aminopeptidases (MAPs) are employed by the cells to cleave the N-terminal methionine from nascent peptides and proteins. The removal of methionine is a critical step in protein maturation as MAP deletion mutants were shown to be lethal for bacteria and yeast. It is therefore very likely that potent and specific MAP inhibitors may prove useful for the design of novel antibacterial agents. In addition, human MAP-2, which is structurally similar to bacterial MAPs, has been demonstrated to be the molecular target of bestatin-derived anti-angiogenesis compounds. Here we present the discovery of novel potent inhibitors of E. coli MAP (EcMAP) - the pyrazole-diamines (PDAs). Successful identification of these new drug prototypes has been greatly facilitated by solving structures of EcMAP with tentative inhibitors during the very early stages of discovery process. Atomic-resolution structures of several PDAs bound to EcMAP illuminate a completely new mode of MAP-inhibitor binding. Combination of the binding mode of PDAs with that of the previously described amino-alcohol inhibitors presents an attractive avenue for further improvement of potency and selectivity of MAP inhibitors.