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Biochemical, Kinetic, and Computational Structural Characterization of Shikimate Kinase from Methicillin-Resistant Staphylococcus Aureus

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Biochemical, Kinetic, and Computational Structural Characterization of Shikimate Kinase from Methicillin-Resistant Staphylococcus Aureus Otorgaa la presente C O N S T A N C I A a: Luis Enrique Pérez Del Castillo Quien asistió y presentó el trabajo: Exploring chemical space to find potential inhibitors of protein tyrosine phosphatase 1B Por: Luis Enrique Pérez del Castillo, Claudia Isela Avitia Domínguez, Marcelo Gómez‐Palacio Gastelum, Jorge Cisneros Martínez, Alfredo Téllez Valeencia En la modalidad de cartel durante el XXXII Congreso Nacional de Bioquímica 4 ‐ 9 de noviembre de 2018 en Ixtapa, Zihuatanejo, Gro. Atentamente Por el Comité Organizador Dra. Irene B. Castaño Navarro Presidente Send Orders for Reprints to [email protected] 260 Current Protein and Peptide Science, 2016, 17, 260-274 Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design Claudia Avitia-Domínguez1, Erick Sierra-Campos2, Irene Betancourt-Conde1, Miriam Aguirre-Raudry1, Alejandra Vázquez-Raygoza1, Artemisa Luevano-De la Cruz1, Alejandro Favela-Candia1, Marie Sarabia-Sanchez1, Lluvia Ríos-Soto1, Edna Méndez-Hernández1, Jorge Cisneros-Martínez1, Marcelo Gómez Palacio-Gastélum3, Mónica Valdez-Solana2, Jessica Hernández-Rivera2, Jaime De Lira-Sánchez2, Mara Campos-Almazán2 and Alfredo Téllez-Valencia1,* 1Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Av. Universidad y Fanny Anitua S/N, Durango. Dgo. México, C.P. 34000; 2Facultad de Ciencias Químicas, Universidad Juárez del Estado de Durango, Av. Artículo 123 S/N Fracc. Filadelfia, Gómez Palacio, Durango, CP. 35010, México; 3Facultad de Odontología, Universi- dad Juárez del Estado de Durango, Predio Canoas S/N, Colonia Los Ángeles, Durango. Dgo. México, C.P. 34070 Abstract: Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. To- day, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in re- cent years with regard to inhibition of enzymes used as targets for drug design against malaria. Keywords: Malaria, Plasmodium falciparum, enzyme inhibition, drug design. 1. INTRODUCTION affects different organs in a very important manner such as cerebral malaria, pulmonary edema, jaundice, acidosis, hy- Malaria is the most important disease caused by a para- poglycemia, severe anemia, and acute kidney injury. In addi- site. According to the last WHO report [1], malaria affects tion, cases of severe malaria caused by P. vivax have been 104 countries, and 3.4 billion people are at risk, an estimated reported in several countries recently [2]. 627 000 deaths occurred and 207 million of new cases were presented in 2012. Africa was the most affected by the 80% Malaria treatment includes a variety of drugs, such as Di- of the cases and the 90% of the deaths, children under 5 hydroartemisinin, Artemether, Artesunate, Piperaquine, Sul- years were the majority of them (77%). Five species of the fadoxine, Lumefantrine, Chloroquine, Quinine, Atovaquone, genus Plasmodium cause malaria, P. knowlesi, P. vivax, P. Mefloquine, Pyrimethamine, Primaquine, Proguanil, Amo- falciparum, P. malariae, and P. ovale. Although P. vivax is diaquine, and Pyronaridine [3]. Because of the development more widely distributed than P. falciparum worldwide, most of resistance to these antimalarials by P. falciparum strains of the deaths are due to falciparum. [4] WHO recommended the use of a combination therapy named ACT (Artemisinin based combination therapy) that Uncomplicated malaria courses with symptoms that includes one Artemisinin derivative plus another drug. Gen- could be confused with another type of common diseases, erally, it was an excellent strategy saving thousands of lives these include abdominal discomfort, irregular fever, fatigue, around the world. However, resistance to ACT or Artemis- vague absence of well-being, and muscle aches, and fre- inin derivatives has been reported [1, 5]. This situation raises quently, vomiting, nausea and orthostatic hypotension are the necessity to find new drugs against malaria. To this end, present. Conversely, severe malaria caused by P. falciparum different macromolecules from P. falciparum have been used as targets for drug discovery. These are quite diverse and *Address correspondence to this author at the Facultad de Medicina y Nu- include enzymes of the respiratory chain in the parasite mi- trición, Universidad Juárez del Estado de Durango, Av. Universidad y tochondria [6], several transport proteins [7], enzymes in the Fanny Anitua S/N, Durango. Dgo. México, C.P. 34000; fatty acid synthetic pathway [8], glycolysis pathway [9], a Tel:/Fax: (+52)6188121687; E-mail: [email protected] number of proteases [10], and DNA replication and regula- 1875-5550/16 $58.00+.00 © 2016 Bentham Science Publishers Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design Current Protein and Peptide Science, 2016, Vol. 17, No. 3 261 tion [11]. Drug-resistant malaria parasites are believed to used include hexokinase [16, 17], phosphoglucose isomerase emerge through mutations in the active sites of drug targets [18], triose phosphate isomerase [19], lactate dehydrogenase [12] or from biochemical changes in the drug receptors. This [20, 21], and enolase [22]. review will focus specifically on the achievements on en- Hexokinase is the first enzyme of glycolysis; it is in- zymes used for this matter, both belonging to a metabolic volved in the glucose phosphorylation [14, 23]. The P. falci- pathway, as well as working alone (Fig. 1). parum HK (PfHK) has a molecular weight of 55.3 kDa and has 24% identity with the human HKs [16]. Therefore, it has 2. GLYCOLYTIC PATHWAY AND LACTATE DE- been considered a drug target (Fig. 1) [16, 23]. In this con- HYDROGENASE text, PfHK inhibitors were identified from a small library of Glycolysis is of great importance for Plasmodium during HK inhibitors [16]. Some of these compounds, such as the intraerythrocytic stage, the parasite depends on the glu- 856002 (Fig. 1, Table 1), exhibited an IC50 <1 µM, in addi- cose as an energy source for ATP production [13]. In addi- tion in vitro studies showed that various of these compounds tion, infected red blood cells consumption of glucose in- inhibited the parasite growth, with an EC50 < 10 µM. Hence, creases substantially at 50-100 times [14], therefore enzymes they suggested the great potential of isobenzothiazoline scaf- from this pathway are excellent drug targets for the search of fold for the development of a therapeutic agent against new inhibitors [15]. Some of the enzymes that have been Plasmodium falciparum. $1 133 5HGEORRG FHOO PHPEUDQH +E &D Ά +RVWF\WRVRO 3.$F " $& 3/& 3DUDVLWHPHPEUDQH */<&2/<6,6 *OXFRVH 7$5*(76 &D Ά F$03 ,3 *O\FRO\VLV DQG/'+ )22'9$&82/( 3I+. (1'2620( 0(3SDWKZD\ +E +E )DWW\ DFLG ELRV\QWKHVLV 5LERVH 3 385,1(6$/9$*( 3/$60(36,16 &<67(,1( *OXFRVH3 3XULQH VDOYDJH HQ]\PHV 3(;(/PLPHWLF (1=<0(6 3OP , 3OP ; 3527($6(6 3I3*, 0LWRFKRQGULDO(7&DQG FRPSRXQGV )UXFWRVH3 3I$'$ )3)3)3 S\ULPLGLQHELRV\QWKHVLV 6\P '1$V\QWKHVLV 6PDOOSHSWLGHV $0,123(37,'$6(6 7UDQVODWLRQDQGSRVWWUDQVODWLRQ 3I0 07FRIRUP\FLQH &RPSRXQG 3I0 PRGL¿FDWLRQV 'LSHSWLGHV '+$3 *3 &\VWHLQH SURWHDVHV 3I7,0 3ODVPHSVLQV 326775$16/$7,21$/ $PLQRSHSWLGDVHV 02',),&$7,216 75$16/$7,21 3I3.$ 3URWHLQ NLQDVHV *3 +LVWRQH O\VLQH $PLQRDFLGV 2WKHU HQ]\PHV %,; (QRODVH PHWK\OWUDQVIHUDVH $%& +DORIXJLQRQH + 3(3 6% +LVWRQHGHDFHW\ODVHV 3RVDFRQD]ROH &RPSRXQGV 1P\ULVWR\O 3527(,1 3I/'+ $PLQRDF\OW51$ .,1$6(6 /DFWDWH 3\UXYDWH WUDQVIHUDVH V\QWKHWDVHV *3 3I&'3. 3I&'3. &D Ά 3(3 (5 0(3 3\UXYDWH " 3$7+:$< 3I';6 3XUIDOFDPLQH %., 16& 18&/(86 $FHW\O &R$ 'HR[\[\OXORVH3 $FHW\O &R$ 3I';5 D &RPSRXQG 27+(5 .& 0HWK\OHU\WKULWRO3 ,VRSUHQH 'LK\GURRURWDWH (1=<0(6 '1$ XQLWV 6<17+(6,6 $FHW\O 0DORQ\O 3I'+2'+ 3I)336 3,5,0,',1(6 0,72&+21'5,21 $&3 $&3 F$03 *33 )33 %<26<17+(6,6 51$ '1$ 2URWDWH 5LVHGURQDWH 3I3'( (7& 3I(15 $03 3 3I'+)5 3I2357 )$77<$&,' 3I6+07 7ULFORVDQ %,26<17+(6,6 7DGDOD¿O )DWW\ DFLGV GHULYDWHV &.3OXPEDJLQ $WRYDTXRQH$OPLWULQH +\GUR[\QDSKWKRTXLQRQHV $3,&23/$67 Fig. (1). Overview of metabolic pathways in P. falciparum. The targets are indicated by numbers in the hexagons, as they were mentioned in the text. 2) Glycolysis and LDH, 3) MEP pathway, 4) Fatty acid biosynthesis, 5) Purine salvage enzymes, 6) Mitochondrial ETC and pyrimidine biosynthesis, 7) DNA synthesis, 8) Translation and post-translation modification, 9) Cysteine proteases, 10) Plasmepsins, 11) Aminopeptidases, 12) Protein kinases, 13) Other enzymes. The inhibitors are marked in the red boxes. Abbreviations: Pf, Plasmodium falci- parum; AN, anion channels; NPP, new permeation pathway; PKAc, cAMP dependent protein kinase A; AC, adenylate cyclase; PLC, phos- pholipase C; IP3, inositol 1,4,5,triphosphate; Hb, haemoglobin; KC, Krebs cycle; MEP, 2 C-methyl-d-erythritol-4-phosphate;
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