Metalloproteins represent a broad class of validated clinical targets, making metalloprotein inhibitors (MPi) an important class of therapeutics.  Indeed, MPi use accounts for billions of dollars in pharmaceutical sales annually and make major contributions to improving human health.  However, the development of MPi lags behind that of conventional small molecule therapeutics, in part because of general concerns about MPi, such as MPi selectivity, as well as the potential for disruption of metal ion homeostasis.  Although these concerns are frequently raised, few studies have directly evaluated these hypotheses.  We have examined the issue of MPi specificity by investigating the selectivity of a variety of MPi against a representative panel of metalloenzymes in the presence of competing metalloproteins and revealed that MPi exhibited excellent selectivity in the presence of large excesses of competing metalloprotein (up to 100-equivalents of competing metalloprotein over the concentration of MPi).  In addition, the capability of multi-element mapping and submicron spatial resolution of synchrotron X-ray fluorescence microscopy (SXRF) makes this method ideal for tracking cellular metal ion distribution.  Herein we used SXRF, SEM-EDX, and ICP-MS to accrue key information regarding the effects of MPi on cellular metal ion homeostasis, which helped to address key questions in MPi design, namely how MPi composition effects metal ion homeostasis and distribution, revealing what factors in the molecular design that merit consideration when developing MPi therapeutics.  We used NIH 3T3 as the model cell system and investigated changes of the three most abundant cellular transition metal ions (Fe, Cu, Zn) in intercellular metal ion trafficking upon exposure of the cells to various of MPi.  Using a suite of cutting edge methods, these studies generated an original data set that is critical for devising design parameters for MPi and understanding the effects of MPi on the ‘metallome’.

Studies on the selectivity of metalloprotein inhibitors and their effects on cellular metal ion homeostasis

251st National Meeting (2016)

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