Inhibition of Schistosoma mansoni carbonic anhydrase by the antiparasitic drug clorsulon: X-ray crystallographic and in vitro studies

Marta Ferraroni,Simone Carradori,Claudiu T Supuran,Andrea Angeli

doi:10.1107/s2059798322000079

Abstract

Clorsulon is an anthelmintic drug that is clinically used against Fasciola hepatica. Due to the presence of two sulfonamide moieties in its core nucleus, which are well recognized as zinc-binding groups, it was proposed that it may be efficacious in the inhibition of parasite carbonic anhydrases (CAs). Proteomic analyses revealed the presence of CA in the tegument of Schistosoma mansoni, and recently the druggability of this target was explored by testing the inhibitory activities of several sulfonamide-based derivatives. According to the principles of drug repurposing, the aim was to demonstrate a putative new mechanism of action of clorsulon and thus widen its antiparasitic spectrum. For this purpose, the inhibitory activity and isoform selectivity of clorsulon was studied using human CA I and S. mansoni CA, revealing different modes of binding of clorsulon that explain its inhibitory potency against the two enzymes. The information obtained in this study could be crucial in the design of more active and selective derivatives.

Highlights

4-Amino-6-(1,2,2-trichlorovinyl)benzene-1,3-disulfonamide, commercially known as clorsulon, is a 1,3-disulfonamide that is structurally similar to 1,3-diphosphoglycerate (Fig. 1) and is able to selectively inhibit parasitic magnesium-containing enzymes implicated in the glycolytic pathway, namely phosphoglycerate kinase (EC 2.7.2.3; PGK 1) and phosphoglyceromutase (EC 5.4.2.11; PGM) (Schulman et al, 1982)
Human carbonic anhydrases (CAs) were better inhibited by AAZ, whereas clorsulon displayed an inferior affinity for hCA I (Ki = 4516 nM) with respect to hCA II, IX and XII
S. mansoni carbonic anhydrase (SmCA) from S. mansoni was strongly affected by clorsulon (Ki = 224.7 nM) and AAZ (Ki = 42.5 nM), despite the latter being more potent

Summary

Introduction

4-Amino-6-(1,2,2-trichlorovinyl)benzene-1,3-disulfonamide, commercially known as clorsulon, is a 1,3-disulfonamide that is structurally similar to 1,3-diphosphoglycerate (Fig. 1) and is able to selectively inhibit parasitic magnesium-containing enzymes implicated in the glycolytic pathway, namely phosphoglycerate kinase (EC 2.7.2.3; PGK 1) and phosphoglyceromutase (EC 5.4.2.11; PGM) (Schulman et al, 1982). It blocks the oxidation of glucose to acetate and propionate (the Embden–Meyerhoff pathway), limiting the primary source of energy in flukes under anaerobic conditions (Martin, 1997; Timson, 2016) It is approved for veterinary use in cattle against adult liver flukes such as Fasciola hepatica and F. gigantica as an oral suspension and by subcutaneous injection (Meaney et al, 2003). Carbonic anhydrases (EC 4.2.1.1) are widespread metalloenzymes that can be clustered into eight families according to their amino-acid characteristics and differences in their active centers. They are present in all living organisms, catalyzing the hydration of carbon dioxide to bicarbonate and a proton (Supuran, 2016a). Its massive use has led to the development of improved resistance, with no alternative options being proposed in recent years (McManus et al, 2018; Wilson, 2020; Siqueira et al, 2017)

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