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The importance of metal binding in metalloprotein inhibitors

  • Author(s): Agrawal, Arpita
  • et al.
Abstract

The development of novel and selective full-length inhibitors against medicinally relevant zinc metalloenzymes has been described. The diversity of zinc metalloenzymes described range from those present in humans to bacteria to viruses. The dissertation will first focus on the development of selective inhibitors against matrix metalloproteinases (MMPs). MMPs are Zn²⁺ hydrolytic enzymes that are present in vertebrates, invertebrates and even plants. They are responsible for the cleavage of the extracellular matrix, and this study demonstrates the importance the zinc-binding group (ZBG) plays in developing inhibitors that are selective against different MMP isoforms. The selectivity obtained from the (O,O) chelating MMP inhibitors (MMPi) was very interesting; considering the active site of MMPs are highly homologous with a conserved Zn²⁺ metal cofactor bound by three histidine residues within a conserved HEXGHXXGXXH metal binding motif. In Chapter 3, the development of full length metalloprotein inhibitors is expanded beyond MMP isoform selectivity to selectivity against another Zn²⁺ endopeptidase, Anthrax lethal factor (LF). This study shows that the potent (O,O) containing MMPi show no inhibition against LF. The bis-histidine and glutamate coordinated catalytic Zn²⁺ in LF favors the softer (O,S) donor ligands. In addition a backbone and linker SAR study shows that a thioamide linkage instead of the traditional amide linkage for backbone attachment introduces a hydrogen bond within the LF active site to enhance potency of the studied inhibitors. Chapter 4 introduces the relatively novel approach of fragment-based lead design (FBLD) in the lab toward the microwave assisted rapid synthesis of a 87-component chelator fragment library that showed potent hits with good ligand efficiencies (LEs) against both MMPs and LF. The final chapter culminates with the study of an entirely new metalloenzyme Human Immunodeficiency Virus Integrase (HIV-IN). As opposed to the mononuclear Zn²⁺ endopeptidases MMPs and LF, HIV-IN is a dinuclear Mg²⁺ endonuclease and preliminary studies show that inhibitors developed against MMPs and LF show submicromolar potencies against this structurally different metalloenzyme. Based on these results, novel HIV -IN inhibitors (HIV-INi) were generated to study the effects of different tris-chelating metal binding groups (MBGs) on this enzyme, while maintaining a constant backbone

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