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Plasmepsin Inhibitors: A View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Publications of the IAS Fellows M. M. Kesavulu Plasmepsin inhibitors: A. S. Prakasha Gowda T. N. C. Ramya design, synthesis, inhibitory N. Surolia studies and crystal structure K. Suguna analysis Authors' affiliations: Key words: malaria; plasmepsins; Plasmodium falciparum; plas- M. M. Kesavulu, A. S. Prakasha Gowda, T. N. C. mepsin inhibition; aspartic protease Ramya and K. Suguna Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India Abstract: Plasmepsin group of enzymes are key enzymes in the life N. Surolia, Jawaharlal Nehru Centre for Advanced cycle of malarial parasites. As inhibition of plasmepsins leads to the Scientific Research, Jakkur, Bangalore, India parasite’s death, these enzymes can be utilized as potential drug targets. Although many drugs are available, it has been observed Correspondence to: K. Suguna that Plasmodium falciparum, the species that causes most of the Molecular Biophysics Unit malarial infections and subsequent death, has developed Indian Institute of Science resistance against most of the drugs. Based on the cleavage sites of Bangalore – 560012 Karnataka, India hemglobin, the substrate for plasmepsins, we have designed two Tel.: 91 80 22932838 compounds (p-nitrobenzoyl-leucine-b-alanine and p-nitrobenzoyl- 91 80 23600535 Fax: leucine-isonipecotic acid), synthesized them, solved their crystal E-mail: [email protected] structures and studied their inhibitory effect using experimental and theoretical (docking) methods. In this paper, we discuss the synthesis, crystal structures and inhibitory nature of these two compounds which have a potential to inhibit plasmepsins. Abbreviations: DCC, dicylohexyl carbodiamide; HAP, histo-asparstic protease; Hb, hemoglobin; HOBt, 1-hydroxybenzotrizole. Introduction Every year, billions of people are infected with malaria and close to 3 million people die because of the disease (1). Malaria is caused by four major species, Plasmodium fal- ciparum, P. vivax, P. malariae, and P. ovale. Among these four major species, P. falciparum alone accounts for more than 95% of the malaria cases (2). Although many anti- malarial drugs are available, both P. falciparum and P. vivax have developed resistance for almost all the available drugs (3,4). Therefore, to find newer antimalarial agents is indeed the need of the hour. The asexual development of the malarial parasite takes place in human erythrocyte or the red blood cell (RBC). During this stage, the parasite utilizes hemoglobin (Hb) of RBC as the only source of food. Three different classes of enzymes present in the food vacuole of the malarial parasite – falcipain (cysteine protease) (5), falcilysin (met- alloprotease) (6) and plasmepsins (aspartic proteases) (7)– are responsible for the digestion of Hb. Of the three dif- ferent classes of enzymes involved in the digestion of Hb, plasmepsins are known to be the key enzymes as they initiate the catalytic breakdown of Hb. Hence, these en- zymes can be probed as potential drug targets. Three aspartic proteases (plasmepsin I, II and IV) and one histo- aspartic protease (HAP) are involved in Hb degradation (8,9). Plasmepsins I and II are involved in the first phase of Hb degradation, while plasmepsin IV and HAP either partially digest Hb or act on the degradation products of the first phase to cleave them into smaller peptides. Re- cent genome data of P. falciparum revealed the presence of six more plasmepsins (plasmepsins V to X) in the parasite. These enzymes share much less similarity among them- selves and with the other four aspartic proteases and their functions are not yet known. Since the identification of plasmepsins in 1994 (10), 1 numerous attempts have been made to design inhibitors of Figure . Chemical structures of (A) p-nitrobenzoyl-leucine-b-alanine (Asp-12) and (B) p-nitrobenzoyl-leucine-isonipecotic acid (Asp-20). plasmepsins with a view to develop them into potent anti- malarial drugs. A wide variety of them have been designed, synthesized, checked for activity by enzyme assays as well synthesized two small compounds (Fig. 1) based on the Hb as in parasite cultures. They include both peptide-like cleavage sites of plasmepsins and also incorporated a b- (7,11,12) and non-peptidyl (4,13,14) inhibitors. Some of them amino acid in one of them and the isonipecotic acid group in were designed based on the substrate structure (Phe33- the other as alternate strategies for inhibitor design with a Leu34 of Hb) (15) and/or statine residue (16) of the universal view to test the feasibility of developing them as effective aspartic protease inhibitor, pepstatin. C2 symmetric (17) and antimalarials. To study the interaction of these compounds achiral inhibitors (4) were also reported. The determination with plasmepsin I, we have crystallized both the com- of the crystal structure of plasmepsin II in complex with pounds, determined their crystal structures and performed pepstatin revealed intricate details of the mode of binding docking studies using the crystal structures, the results of and provided a platform for the structure-based design (18). which are presented in this paper. Subsequent crystal structures of plasmemsin II with other inhibitors (13,15) revealed the conformational flexibility of the binding pocket and an entirely new type of binding (19). Experimental Procedures Modeling/docking, molecular dynamics and interaction energy calculations were also performed in many studies Synthesis of compounds (4,17). Some of the compounds could successfully inhibit the enzyme but failed to stop the parasite growth in cell The compounds were synthesized by the stepwise solution- culture (4,7,18) probably because of their size that prevents phase method. Dicyclo hexylcarbodiamide (DCC) was used the access to the food vacuole of the parasite where the Hb for the formation of the peptide bond. degradation occurs. The strategy for a viable drug is to find a relatively small, cost-effective and highly specific inhibitor. p-(NO2)-Ba-(L),(D)-Leu-b-Ala-OMe (Asp-12 & Asp-13) Although many inhibitors targeting the plasmepsin group of p-(NO2)-Ba-(l)-Leu-OH or p-(NO2)-Ba-(d)-Leu-OH (0.9 g, enzymes are available, none of them are in use as drugs for 3.21 mm) was dissolved in 10 mL of ethyl acetate and the treatment of malaria today. We have designed and cooled to 0 °C in an ice bath. H-b-Ala-OMe, isolated from Table 1. Details of crystal data, data collection and refinement parameters Asp-12/Asp-13 Asp-20/Asp-21 Empirical formula C17H23N3O6 C20H27N3O6 Crystal size (mm) 0.44 · 0.19 · 0.09 0.2 · 0.17 · 0.1 Crystallizing solvent Acetone Acetone Crystal system Triclinic Monoclinic Space group P 1 C 1 2/c 1 Unit cell dimensions a (A˚ ) 8.791(3) 17.246(4) b (A˚ ) 9.725(3) 12.800(3) c (A˚ ) 11.165(4) 19.708(4) a (°) 92.231(6) 90 b (°) 95.723(6) 96.138(5) c (°) 98.977(6) 90 Volume (A˚ 3) 936.7(13) 4325.36(29) Z 28 Mr 365.4 405.5 Density (g/cm3) (cal) 1.3 1.25 F(000) 387.9 1727.7 2 12 13 Radiation (k in A˚ ) MoKa (0.71073) MoKa (0.71073) Figure . Molecular conformation of (A) Asp- &Asp- and (B) Asp-20. The thermal ellipsoids are at 50% probability level. Temperature (°C) 20 25 Unique reflections 3913 2278 p-(NO2)-Ba-(L),(D)-Leu-Ina-OMe (Asp-20 & Asp-21) l d 0 28 Observed reflections 3023 1374 p-(NO2)-Ba-( )-Leu-OH or p-(NO2)-Ba-( )-Leu-OH ( . g, 1 0 m 5 Final R (%) 3.63 6.76 . m ) was dissolved in mL of ethyl acetate and cooled to 0 Final wR2 (%) 7.56 14.62 °C in an ice bath. H-Ina-OMe (Ina-isonipecotic acid), iso- 0 28 2 0 m 2 Goodness of fit (S) 0.957 1.009 lated from . g(. m , eq.) of hydrochloride was )3 neutralized, followed by extraction with ethyl acetate, and Dqmax (e A˚ ) 0.120 0.428 )3 concentration to approximately 5 mL. It was then added to p- Dqmin (e A˚ ) )0.093 )0.154 Data-to-param ratio 8.2:1 8.5:1 (NO2)-Ba-Leu-OH under stirring while maintaining the temperature at 0 °C, followed immediately by the addition of DCC/HOBt of 0.21 g(1.0 mm)/0.14 g(1.0 mm). The reaction 0.7 g(6.42 mm, 2 eq.) of hydrochloride was neutralized, mixture was allowed to reach room temperature and stirred followed by extraction with ethyl acetate and concentration for 3–4 h. The precipitated dicyclohexylurea was filtered off. to approximately 5 mL. It was then added to p-(NO2)-Ba- The organic layer was washed successively with 2 n HCl Leu-OH under stirring while maintaining the temperature (3 · 50 mL), brine (3 · 50 mL), 1 m sodium carbonate at 0 °C, followed immediately by the addition of DCC/1- (3 · 50 mL) and brine (3 · 50 mL). This layer was then dried hydroxybenzotrizole (HOBt) of 0.70 g(3.21 mm)/0.43 g over anhydrous sodium sulfate and was evaporated to yield a (3.21 mm). The reaction mixture was allowed to reach room white solid. The crude peptide was recrystalized from pet- temperature and stirred for 3–4 h. The precipitated dic- roleum ether to obtain Asp-20/Asp-21. The sample was yclohexylurea was filtered off. The organic layer was wa- purified over silica gel using chloroform–methanol as an shed successively with 2 n HCl (3 · 50 mL), brine elutant to yield 0.35 g(0.86 mm, 86.30%) of Asp-20/Asp-21. (3 · 50 mL), 1 m sodium carbonate (3 · 50 mL) and brine (3 · 50 mL).
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