The β-carbonic anhydrase from the malaria mosquito Anopheles gambiae is highly inhibited by sulfonamides. Issue 10 (15th May 2015)

• Record Type: Journal Article
• Authors: Syrjänen, Leo; Kuuslahti, Marianne; Tolvanen, Martti; Vullo, Daniela; Parkkila, Seppo; Supuran, Claudiu T.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 10(2015)
• Page Start: 2303
• Page End: 2309
• Publication Date: 2015-05-15
• Subjects: Carbonic anhydrase -- β-Class enzyme -- Sulfonamide -- Anopheles gambiae -- Malaria; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.03.081
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: A β-carbonic anhydrase (CA, EC 4.2.1.1) was cloned, purified and characterized from Anopheles gambiae, the mosquito species mainly involved in the transmission of malaria. The new enzyme, AgaCA, showed a significant catalytic activity for the physiologic reaction, CO2 hydration to bicarbonate and protons, with a k cat of 7.2 × 10 5 s −1 and k cat / K m of 5.6 × 10 7 M −1 s −1, being thus similar to parasite β-CAs which were discovered earlier as drug targets for antifungal or anti-protozoan agents. An inhibition study of AgaCA with a panel of aromatic, aliphatic and heterocyclic sulfonamides allowed us to identify several low nanomolar inhibitors of the enzyme. Benzolamide and aminobenzolamide showed inhibition constants of 6.8–9.8 nM, whereas a structurally related aromatic derivative, 4-(2-hydroxymethyl-4-nitrophenyl-sulfonamidoethyl)-benzenesulfonamide was the strongest inhibitor with a K I of 6.1 nM. As β-CAs are not present in mammals, including humans, finding effective and selective A. gambiae CA inhibitors may lead to alternative procedures for controlling malaria by impairing the growth of its transmission vector, the mosquito.