Sulfonamide Inhibition Studies of an α-Carbonic Anhydrase from Schistosoma mansoni, a Platyhelminth Parasite Responsible for Schistosomiasis

Abstract

Schistosomiasis is a debilitating infection provoked by parasitic flatworms called schistosomes. The species Schistosoma mansoni is endemic in Africa, where it causes intestinal schistosomiasis. Recently, an α-carbonic anhydrase (CA, EC 4.2.1.1) was cloned and characterized from this organism and designated as SmCA. The protein is expressed in the tegument (skin) of S. mansoni at the host-parasite interface. Recombinant SmCA possesses high catalytic activity in the CO 2 hydration reaction, similar to that of human CA isoform II with a k cat of 1.2 × 10 6 s −1 and a k cat /K M of 1.3 × 10 8 M −1 ·s −1 . It has been found that schistosomes whose SmCA gene is suppressed using RNA interference are unable to establish a robust infection in mice, suggesting that the chemicals that inhibit SmCA function should have the same debilitating effect on the parasites. In this study, a collection of aromatic/heterocyclic sulfonamides were investigated as possible SmCA inhibitors. Several sulfonamides inhibited SmCA with medium to weak potency (K I values of 737.2 nM−9.25 µM), whereas some heterocyclic compounds inhibited the enzyme with K I values in the range of 124−325 nM. The α-CA from S. mansoni, SmCA, is proposed as a new anti-schistosomiasis drug target.

Know your enemy – transcriptome of myxozoanTetracapsuloides bryosalmonaereveals potential drug targets against proliferative kidney disease in salmonids

“…The third drug target, Carbonic anhydrase 2 (CA2), belongs to the plasma membrane anchored alpha carbonic anhydrases, which catalyse the reversible hydration of carbon dioxide and aid in intracellular pH regulation. Carbonic anhydrases are considered as potent anti-parasitic drug targets against protists, such as Trypanosoma , Leishmania (Vermelho et al ., 2017) and, recently, against blood flukes, schistosomes (Da'dara et al ., 2019; Angeli et al ., 2020). In the predicted three-dimensional model, the active site- and Zn binding residues of T. bryosalmonae CA2 retained similar positions as in SmCA, suggesting that similar therapeutic inhibitors may be used to target this protein in T. bryosalmonae .…”

“…The schistosome alpha carbonic anhydrase plays a role in parasite virulence as its suppression using RNAi significantly reduced the establishment of parasite within host (Da'dara et al ., 2019). Several sulphonamide, thiol and hydroxamate substances have been shown to inhibit CA2 in Trypanosoma and Leishmania schistosomes (Vermelho et al ., 2017; Angeli et al ., 2020).…”

Development of a High-Throughput Affinity Mass Spectrometry (AMS) Platform Using Laser Diode Thermal Desorption Ionization Coupled to Mass Spectrometry (LDTD-MS)

“…5 ). Furthermore, studies by several groups 45–48 have reported the discovery of various aryl sulfonamide-based inhibitors for different isoforms of CA.…”

Development of Praziquantel sulphonamide derivatives as antischistosomal drugs

“…CAs are a superfamily of ubiquitous zinc metalloenzymes, present in all kingdoms of life, and encoded by at least eight distinct, evolutionarily unrelated gene families (designated α , β , γ , δ , ζ , η , θ and ι ) converging in the same crucial reaction, the reverse hydration of CO 2 to H + and HCO 3 − 15–18 . Recently our group reported the key molecular features of CA inhibitors (CAIs) binding to SmCA in comparison with human hCA II in order to understand the structural determinants directing affinity and selectivity 19 , 20 . Here, we report on the development of SmCA inhibitors conjugated to the PZQ scaffold as a possible novel therapeutic target for schistosomiasis.…”