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 <i>Schistosoma mansoni</i> 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 <i>S</i>. <i>mansoni</i> at the host-parasite interface. Recombinant SmCA possesses high catalytic activity in the CO₂ hydration reaction, similar to that of human CA isoform II with a k_cat of 1.2 × 10⁶ s^-1 and a k_cat/K_M of 1.3 × 10⁸ 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 <i>S. mansoni</i>, SmCA, is proposed as a new anti-schistosomiasis drug target.