Beta-Carbonic Anhydrase 1 from Trichomonas Vaginalis as New Antiprotozoan Drug Target

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

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Carbonic anhydrase as drug target – thermodynamics and structure of inhibitor binding

Crystallography Reviews ◽

10.1080/0889311x.2021.2008379 ◽

2021 ◽

pp. 1-2

Author(s):

Franz-Josef Meyer-Almes

Keyword(s):

Carbonic Anhydrase ◽

Drug Target ◽

Inhibitor Binding

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Trifluoromethionine, a Prodrug Designed against Methionine γ-Lyase-Containing Pathogens, Has Efficacy In Vitro and In Vivo against Trichomonas vaginalis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.6.1743-1745.2001 ◽

2001 ◽

Vol 45 (6) ◽

pp. 1743-1745 ◽

Cited By ~ 49

Author(s):

Graham H. Coombs ◽

Jeremy C. Mottram

Keyword(s):

Drug Target ◽

Trichomonas Vaginalis ◽

Anaerobic Bacteria ◽

Protozoan Parasite ◽

Chemotherapeutic Agents ◽

Single Step ◽

Lesion Formation ◽

Highly Active

ABSTRACT Methionine γ-lyase, the enzyme which catalyzes the single-step conversion of methionine to α-ketobutyrate, ammonia, and methanethiol, is highly active in many anaerobic pathogenic microorganisms but has no counterpart in mammals. This study tested the hypothesis that this pathogen-specific enzyme can be exploited as a drug target by prodrugs that are exclusively activated by it. Trifluoromethionine was confirmed as such a prodrug and shown to be highly toxic in vitro to the anaerobic protozoan parasiteTrichomonas vaginalis, to anaerobic bacteria containing methionine γ-lyase, and to Escherichia coli expressing the trichomonad gene. The compound also has exceptional activity against the parasite growing in vivo, with a single dose preventing lesion formation in five of the six mice challenged. These findings suggest that trifluoromethionine represents a lead compound for a novel class of anti-infective drugs with potential as chemotherapeutic agents against a range of prokaryotic and eukaryotic anaerobic pathogens.

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