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Review
. 2023 Jun 19;16(6):901.
doi: 10.3390/ph16060901.

Targeting Metalloenzymes: The "Achilles' Heel" of Viruses and Parasites

Dimitrios Moianos  1 , Georgia-Myrto Prifti  1 , Maria Makri  1 , Grigoris Zoidis  1
Affiliations
Review

Targeting Metalloenzymes: The "Achilles' Heel" of Viruses and Parasites

Dimitrios Moianos et al. Pharmaceuticals (Basel). .

Abstract

Metalloenzymes are central to the regulation of a wide range of essential viral and parasitic functions, including protein degradation, nucleic acid modification, and many others. Given the impact of infectious diseases on human health, inhibiting metalloenzymes offers an attractive approach to disease therapy. Metal-chelating agents have been expansively studied as antivirals and antiparasitics, resulting in important classes of metal-dependent enzyme inhibitors. This review provides the recent advances in targeting the metalloenzymes of viruses and parasites that impose a significant burden on global public health, including influenza A and B, hepatitis B and C, and human immunodeficiency viruses as well as Trypanosoma brucei and Trypanosoma cruzi.

Keywords: HBV; HCV; HIV; Trypanosoma brucei; Trypanosoma cruzi; antiparasitic agents; antiviral agents; influenza A; metal chelators; metalloenzymes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structures of reported influenza PAN inhibitors. Arrows indicate the optimization process of lead compounds 1 and 2a to yield compound 4 (and its analogs) and Baloxavir marboxil, respectively. Metal-chelating atoms are highlighted in red.
Figure 2
Figure 2
Interactions of compound 24 with key amino acids of the PAN active site (PDB: 6E4C). Compound 24 chelates the divalent cations of the active site and forms solvent-mediated or direct hydrogen bonding interactions with Lys34, Arg124, and/or Arg196. Mn2+ ions and water molecules are shown with purple and red spheres, respectively. Metal coordination and hydrogen bonds are represented by dashed yellow lines. Reprinted/adapted with permission from Ref. [32]. Copyright © 2023, American Chemical Society.
Figure 3
Figure 3
Predicted poses of Compound 20 (A) and ZINC15340668 (B) in the PAN binding site. In both images, divalent cations are presented as purple spheres. Reprinted/adapted with permission from Ref. [33]. Copyright © 2023, Elsevier, [34]. Copyright © 2023, Elsevier.
Figure 4
Figure 4
Binding pose of compounds 14 (A), 19 (B), and 13e (C) in PAN binding site according to docking calculations. Divalent cations are presented as purple spheres. Reprinted/adapted with permission from Ref. [38] Copyright © 2023, Elsevier and [42] Copyright © 2023, Elsevier.
Figure 5
Figure 5
Structures of reported HCV NS5B inhibitors. Metal-chelating atoms/groups are highlighted in red.
Figure 6
Figure 6
(A) Predicted binding orientation of compound 24 in the catalytic site of HCV polymerase. (B) Two-dimensional diagram of the interactions between the inhibitor and the polymerase’s active site. Docking illustrated the existence of a lipophilic cavity (indicated with yellow arrows) adjacent to the enzyme catalytic pocket. Reprinted/adapted with permission from Ref. [30]. Copyright © 2023, Royal Society of Chemistry.
Figure 7
Figure 7
The active adamantane spiro derivatives and amantadine and rimantadine, two known antiviral agents against influenza A.
Figure 8
Figure 8
Compounds 16, 17, and 11. Some of the most promising agents against T. brucei parasites. Metal-chelating atoms/groups are highlighted in red.
Figure 9
Figure 9
Spiro carbocyclic 2,6-DKP-1-acetohydroxamic acid analogues. Metal-chelating atoms/groups are highlighted in red.
Figure 10
Figure 10
DFO and 1,10-phenanthroline were the first reported iron-chelating inhibitors of iron-dependent enzymes in T. brucei species.
Figure 11
Figure 11
Three new generation iron chelators of four iron-dependent T. brucei enzymes. Metal-chelating atoms/groups are highlighted in red.
Figure 12
Figure 12
Chemical structures of AAZ, MZA, SLT, SLP, and EZA, which are known from literature, and novel sulfonamide inhibitors examined for their trypanocidal activity with promising results. Metal-chelating atoms/groups are highlighted in red.
Figure 13
Figure 13
Hydroxamic acid analogue with significant potency and selectivity for T. cruzi parasites was found to be more active than clinical drug benzidazole. Metal-chelating atoms/groups are highlighted in red.
Figure 14
Figure 14
Compound 7d was proven to be the most active among all of the compounds tested, with an IC50 = 0.21 μΜ.
Figure 15
Figure 15
Novel secondary hydroxamic acid derivatives and their potent counterparts. Metal-chelating atoms/groups are highlighted in red.
Figure 16
Figure 16
Metal chelators with dual activity, both trypanocidal and antiviral. Metal-chelating atoms/groups are highlighted in red.
Figure 17
Figure 17
Best dithiocarbamate derivatives acting as metal chelators for zinc-, iron-, and copper-dependent T. cruzi enzymes. Metal-chelating atoms are highlighted in red.
Figure 18
Figure 18
Crystal structures of the complex of RNaseH active site and compounds (a–f). Mn2+ ions are presented as spheres in purple. Reprinted/adapted with permission from Ref. [160]. Copyright © 2023, American Chemical Society.
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