Roth, Lukas
Abstract:
Immobilized Metal Affinity Chromatography as a Potential Drug Discovery Platform
Topic:
In 1990, approximately 80% of medicines approved in the U.S. were either natural products or their derivatives. In the early 2000s there was a significant drop in the number of natural products in clinical studies, coinciding with the expansion of high throughput screening (HTS) techniques. However, the limited structural diversity inherent to HTS and the emerging threat of antimicrobial resistance has reinvigorated the focus on exploiting natural products for the discovery and development of new medicines. Immobilized metal affinity chromatography (IMAC), a technique originally designed for the isolation of histidinetagged proteins, has shown promise in isolating and purifying bioactive compounds. IMAC relies on the fundamentals of coordination chemistry to reversibly retain compounds with known metal ion affinity. Although originally developed for recombinant protein purification, this simple method has been shown to readily purify hydroxamic acid siderophores, such as desferrioxamine B (DFOB) and other clinical agents, from bacterial cultures. Most IMAC work, in the context of siderophore isolation and purification, has utilized Ni(II) as the metal ion, but there is potential in substituting Ni(II) with other metal ions, such as Cu(II), Fe(III), Ga(III) and Zn(II). The modified IMAC resin beds may consequently act as metalloenzyme surrogates and select for different metabolites as directed by distinct coordination chemistries. This could open up a new platform to discover metalloenzyme inhibitor drug candidates as the isolated metabolites, by virtue of their metal binding affinity, may demonstrate activity against various metalloenzymes. As an initial proof of concept, we have exposed a mixture of in use metalloenzyme inhibitors to IMAC columns charged with various biologically relevant metals with promising results. The IMAC ligand-metal complex is a reasonable surrogate of the active site of a metalloenzyme and the method is capable of reversibly binding a variety of antihypertensive, anti-inflammatory and anticancer drugs.
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