Inhibitors of Hydrolyzing Metalloenzymes

In metalloproteases, a positively charged metal ion, usually zinc, activates a coordinated water molecule that nucleophilically attacks the peptide bond to be cleaved. By expanding its coordinating sphere, the zinc ion also polarizes the carbonyl group of the amide bond to be cleaved, and an adjacent glutamate residue helps to transfer protons. Potent inhibitors have appropriate functional groups to coordinate the zinc ion and bind to the specificity pockets on the primed side that recognize the C-terminal part of the substrate to be cleaved. Angiotensin converting enzyme (ACE) converts angiotensin I to angiotensin II by cleaving a C-terminal dipeptide. Dipeptide mimetics with a carboxylate group on a proline-like moiety and a zinc coordinating group at the opposite end have emerged from rational design concepts. Captopril was the first compound to enter therapy. It was followed by a large number of ACE inhibitors. ACE consists of two slightly different catalytic domains. In addition to angiotensin I, ACE also degrades other peptides, such as bradykinin, which lowers blood pressure. The undesirable side effects of ACE inhibitors are related to this degradation. The two domains of ACE have different substrate profiles, which can be translated into selective inhibition of ACE. Matrix metalloproteases (MMPs) are a large family of structurally related neutral zinc endopeptidases. They are involved in the formation and degradation of connective tissue. The adaptive nature of the binding pockets of these proteins and the highly overlapping substrate profiles have made the development of selective MMP inhibitors extremely difficult. Different members of the family can mutually take over the role of the protease to be inhibited. Carbonic anhydrases are hydrolases that convert carbon dioxide to bicarbonate. They catalyze important processes such as respiration, CO2 transport, pH homeostasis, electrolyte secretion, supply of C1 building blocks, bone resorption and calcification, or tumor growth. Due to the narrow funnel-shaped architecture of the enzyme with the catalytic zinc ion at the end, almost all carbonic anhydrase inhibitors have a terminal sulfonamide group. In particular, diuretics and antiglaucoma agents have been marketed. These drugs lower intraocular pressure. Phosphodiesterases (PDEs) are a small family of metalloenzymes. They hydrolyze the second messengers cAMP and cGMP. Inhibitors of the PDE 5 isoform, such as sildenafil, originally developed for the treatment of angina pectoris, have been shown to stimulate penile erection by inhibiting cGMP degradation. Under reductive conditions, iron (II) ions are found instead of zinc ions in the catalytic center of hydrolyzing enzymes. In peptide deformylases, the iron ion plays a similar role to the zinc ion. Inhibitors of peptide deformylases are either potential antibiotics or can be exploited for their antineoplastic effects. Histone deacetylases (HDACs) remove the acetyl group from the terminal nitrogen of an acetylated lysine, thereby restoring the basicity and positive charge of the terminal amino group. Histone proteins serve to efficiently coil the negatively charged DNA in the nucleus. The enhanced electrostatic interactions with the charged lysine residues result in increased DNA binding. As a result, the gene information on the DNA cannot be efficiently read by the transcription factors. Gene expression is thus repressed. HDAC inhibitors attempt to interfere with the reading of DNA in the case of misregulation of gene expression. For this reason, they can be used in many diseases, especially in tumor diseases. https://sn.pub/cy407x