Malaria remains one of the most important diseases in developing countries. Plasmodium falciparum (Pf), the etiological agent of malaria, is developing an increasing resistance to traditional drugs, like chloroquine (CQ). Consequently, the development of new antimalarial agents able to overcome CQ-resistance is an urgent task to be accomplished. The antifungal agent clotrimazole (CLT) has been shown to have a moderate growth-inhibiting effect on different Pf strains (1), and it has been taken as a model for the rational design of innovative classes of antimalarial agents (2). We have previously shown that CLT is able to inhibit the SERCA1 (SR-CaATPase) (3). Here we present some results concerning the effect on SERCA1 of NF1058 (4), a novel compound with potent antimalarial properties that possesses key structural elements of both CLT and CQ. We used an approach that combines biochemical and electrical techniques. Our data show that NF1058 inhibits the steady-state hydrolytic activity of the pump with a medium affinity (K0.5 = 41 ± 1 microM), but it does not interfere with Ca-binding to the enzyme. We therefore suggest that the reduction of steady-state hydrolytic activity of SERCA1 by NF1058 may be due to an interference with the Ca-release process. We are planning to explore the possibility that NF1058 can inhibit PfATP6, a SERCA-type ATPase expressed by the plasmodium. Ente Cassa di Risparmio di Firenze is acknowledged for financial support. 1. T. Tiffert et al., Proc. Natl. Acad. Sci. U. S. A. 97 (2000) 331-336 2. S. Gemma et al., J. Med. Chem. 52 (2009) 502-513 3. G. Bartolommei et al., J. Biol. Chem. 281 (2006) 9547-9551 4. G. Campiani et al., WO 2008/101891
Inhibition of SERCA1 by a Novel Antimalarial Compound / G. Bartolommei; F. Tadini-Buoninsegni; S. Gemma; C. Camodeca; S. Butini; G. Campiani; M.R. Moncelli. - In: BIOPHYSICAL JOURNAL. - ISSN 0006-3495. - STAMPA. - 98:(2010), pp. 505a-505a. (Intervento presentato al convegno Biophysical Meeting 2010 tenutosi a San Francisco, CA - USA nel February 20-24, 2010).