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

International Journal of Molecular Sciences
Andrea AngeliClaudiu T Supuran

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 CO2 hydration reaction, similar to that of human CA isoform II with a kcat of 1.2 × 106 s-1 and a kcat/KM 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 (KI values of 737.2 nM-9.25 μM), whereas some heterocyclic compounds inhibited the enzyme with KI values in the range of 124-325 nM. The α-CA from S. mansoni, SmCA, is proposed as a new anti-schistosomiasis drug tar...Continue Reading

References

Jan 3, 2008·Nature Reviews. Drug Discovery·Claudiu T Supuran
Nov 4, 2008·Current Opinion in Infectious Diseases·Michael J DoenhoffJürg Utzinger
Sep 17, 2011·Nature Reviews. Drug Discovery·Dario Neri, Claudiu T Supuran
Oct 12, 2012·Parasitology Research·Wei WangYou-Sheng Liang
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Feb 6, 2013·Journal of Enzyme Inhibition and Medicinal Chemistry·Claudiu T Supuran
Apr 29, 2014·Journal of Enzyme Inhibition and Medicinal Chemistry·Clemente Capasso, Claudiu T Supuran
Aug 30, 2014·Bioorganic & Medicinal Chemistry Letters·Sonia Del PreteClaudiu T Supuran
Dec 2, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Claudiu T Supuran
Jul 14, 2016·The Biochemical Journal·Claudiu T Supuran
Oct 27, 2016·Expert Opinion on Drug Discovery·Claudiu T Supuran
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Sep 16, 2018·Expert Opinion on Therapeutic Patents·Claudiu T Supuran
Oct 23, 2018·ACS Medicinal Chemistry Letters·Andrea AngeliClaudiu T Supuran
Dec 19, 2018·Chemical Communications : Chem Comm·Andrea AngeliClaudiu T Supuran
Feb 8, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Andrea AngeliClaudiu T Supuran
Feb 9, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Andrea AngeliClaudiu T Supuran
Apr 27, 2019·The ISME Journal·Erik L JensenBrigitte Gontero
Oct 18, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Manuel A LlanosLuciana Gavernet
Nov 7, 2019·European Journal of Medicinal Chemistry·Damiano TaniniClaudiu T Supuran

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Datasets Mentioned

BETA
MK611932

Methods Mentioned

BETA
Protein Assay

Software Mentioned

PRISM

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