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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

In Silico Analysis of Potential Drug Targets for Protozoan Infections

Author(s): Alfredo Juárez-Saldivar, Nuria E. Campillo, Eyra Ortiz-Perez, Alma D. Paz-Gonzalez, Emma Saavedra and Gildardo Rivera*

Volume 19, Issue 1, 2023

Published on: 07 September, 2022

Page: [91 - 98] Pages: 8

DOI: 10.2174/1573406418666220816121912

Price: $65

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Abstract

Background: Currently, protozoan infectious diseases affect billions of people every year. Their pharmacological treatments offer few alternatives and are restrictive due to undesirable side effects and parasite drug resistance.

Objective: In this work, three ontology-based approaches were used to identify shared potential drug targets in five species of protozoa.

Methods: In this study, proteomes of five species of protozoa: Entamoeba histolytica (E. histolytica), Giardia lamblia (G. lamblia), Trichomonas vaginalis (T. vaginalis), Trypanosoma cruzi (T. cruzi), and Leishmania mexicana (L. mexicana), were compared through orthology inference using three different tools to identify potential drug targets.

Results: Comparing the proteomes of E. histolytica, G. lamblia, T. vaginalis, T. cruzi, and L. mexicana, twelve targets for developing new drugs with antiprotozoal activity were identified.

Conclusion: New drug targets were identified by orthology-based analysis; therefore, they could be considered for the development of new broad-spectrum antiprotozoal drugs. Particularly, triosephosphate isomerase emerges as a common target in trypanosomatids and amitochondriate parasites.

Keywords: Drug target, protozoa, orthology, infectious disease, trypanosomatid, amitochondriates

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[1]
Leung, A.K.C.; Leung, A.A.M.; Wong, A.H.C.; Hon, K.L. Travelers’ diarrhea: A clinical review. Recent Pat. Inflamm. Allergy Drug Discov., 2019, 13(1), 38-48.
[http://dx.doi.org/10.2174/1872213X13666190514105054] [PMID: 31084597]
[2]
Molyneux, D.H.; Savioli, L.; Engels, D. Neglected tropical diseases: Progress towards addressing the chronic pandemic. Lancet, 2017, 389(10066), 312-325.
[http://dx.doi.org/10.1016/S0140-6736(16)30171-4] [PMID: 27639954]
[3]
Ghorbani, M.; Farhoudi, R. Leishmaniasis in humans: Drug or vaccine therapy? Drug Des. Devel. Ther., 2017, 12, 25-40.
[http://dx.doi.org/10.2147/DDDT.S146521] [PMID: 29317800]
[4]
Pérez-Molina, J.A.; Molina, I. Chagas disease. Lancet, 2018, 391(10115), 82-94.
[http://dx.doi.org/10.1016/S0140-6736(17)31612-4] [PMID: 28673423]
[5]
Smirlis, D.; Soares, M.B. Selection of molecular targets for drug development against trypanosomatids. Subcell. Biochem., 2014, 71, 43-76.
[http://dx.doi.org/10.1007/978-94-007-7305-9_2] [PMID: 24264240]
[6]
Teixeira, S.M.; Paiva, R.M.C. d; Kangussu-Marcolino, M.M.; DaRocha, W.D. Trypanosomatid comparative genomics: Contributions to the study of parasite biology and different parasitic diseases. Genet. Mol. Biol., 2012, 35, 1-17.
[http://dx.doi.org/10.1590/s1415-47572012005000008] [PMID: 22481868]
[7]
Berriman, M. Data mining parasite genomes. Parasitology, 2004, 128(S1), S23-S31.
[http://dx.doi.org/10.1017/S0031182004006857] [PMID: 16454895]
[8]
Sateriale, A.; Bessoff, K.; Sarkar, I.N.; Huston, C.D. Drug repurposing: Mining protozoan proteomes for targets of known bioactive com-pounds. J. Am. Med. Inform. Assoc., 2014, 21(2), 238-244.
[http://dx.doi.org/10.1136/amiajnl-2013-001700] [PMID: 23757409]
[9]
Kotowski, N.; Jardim, R.; Dávila, A.M.R. Improved orthologous databases to ease protozoan targets inference. Parasit. Vectors, 2015, 8(1), 494.
[http://dx.doi.org/10.1186/s13071-015-1090-0] [PMID: 26416523]
[10]
Cuadrat, R.R.; da Serra Cruz, S.M.; Tschoeke, D.A.; Silva, E.; Tosta, F.; Jucá, H.; Jardim, R.; Campos, M.L.; Mattoso, M.; Dávila, A.M. An orthology-based analysis of pathogenic protozoa impacting global health: An improved comparative genomics approach with prokaryotes and model eukaryote orthologs. OMICS, 2014, 18(8), 524-538.
[http://dx.doi.org/10.1089/omi.2013.0172] [PMID: 24960463]
[11]
Campos, D.A.; Pereira, E.C.; Jardim, R.; Cuadrat, R.R.; Bernardes, J.S.; Dávila, A.M. Homology inference based on a reconciliation approach for the comparative genomics of Protozoa. Evol. Bioinform. Online, 2018, 14, 1176934318785138.
[http://dx.doi.org/10.1177/1176934318785138] [PMID: 30034216]
[12]
Bateman, A.; Martin, M.-J.; Orchard, S.; Magrane, M.; Agivetova, R.; Ahmad, S.; Alpi, E.; Bowler-Barnett, E.H.; Britto, R.; Bursteinas, B.; Bye-A-Jee, H.; Coetzee, R.; Cukura, A.; Da Silva, A.; Denny, P.; Dogan, T.; Ebenezer, T.G.; Fan, J.; Castro, L.G.; Garmiri, P.; Georghiou, G.; Gonzales, L.; Hatton-Ellis, E.; Hussein, A.; Ignatchenko, A.; Insana, G.; Ishtiaq, R.; Jokinen, P.; Joshi, V.; Jyothi, D.; Lock, A.; Lopez, R.; Luciani, A.; Luo, J.; Lussi, Y.; MacDougall, A.; Madeira, F.; Mahmoudy, M.; Menchi, M.; Mishra, A.; Moulang, K.; Nightingale, A.; Oliveira, C.S.; Pundir, S.; Qi, G.; Raj, S.; Rice, D.; Lopez, M.R.; Saidi, R.; Sampson, J.; Sawford, T.; Speretta, E.; Turner, E.; Tyagi, N.; Vasudev, P.; Volynkin, V.; Warner, K.; Watkins, X.; Zaru, R.; Zellner, H.; Bridge, A.; Poux, S.; Redaschi, N.; Aimo, L.; Argoud-Puy, G.; Auchincloss, A.; Axelsen, K.; Bansal, P.; Baratin, D.; Blatter, M-C.; Bolleman, J.; Boutet, E.; Breuza, L.; Casals-Casas, C.; de Castro, E.; Echioukh, K.C.; Coudert, E.; Cuche, B.; Doche, M.; Dornevil, D.; Estreicher, A.; Famiglietti, M.L.; Feuermann, M.; Gasteiger, E.; Gehant, S.; Gerritsen, V.; Gos, A.; Gruaz-Gumowski, N.; Hinz, U.; Hulo, C.; Hyka-Nouspikel, N.; Jungo, F.; Keller, G.; Kerhornou, A.; Lara, V.; Le Mercier, P.; Lieberherr, D.; Lombardot, T.; Martin, X.; Masson, P.; Morgat, A.; Neto, T.B.; Paesano, S.; Pedruzzi, I.; Pilbout, S.; Pour-cel, L.; Pozzato, M.; Pruess, M.; Rivoire, C.; Sigrist, C.; Sonesson, K.; Stutz, A.; Sundaram, S.; Tognolli, M.; Verbregue, L.; Wu, C.H.; Arighi, C.N.; Arminski, L.; Chen, C.; Chen, Y.; Garavelli, J.S.; Huang, H.; Laiho, K.; McGarvey, P.; Natale, D.A.; Ross, K.; Vinayaka, C.R.; Wang, Q.; Wang, Y.; Yeh, L.-S.; Zhang, J.; Ruch, P.; Teodoro, D. UniProt: The universal protein knowledgebase in 2021. Nucleic Acids Res., 2021, 49(D1), D480-D489.
[http://dx.doi.org/10.1093/nar/gkaa1100] [PMID: 33237286]
[13]
Moriya, Y.; Itoh, M.; Okuda, S.; Yoshizawa, A.C.; Kanehisa, M. KAAS: An automatic genome annotation and pathway reconstruction server. Nucleic Acids Res., 2007, 35(Suppl. 2), W182-5.
[http://dx.doi.org/10.1093/nar/gkm321] [PMID: 17526522]
[14]
Li, L.; Stoeckert, C.J., Jr.; Roos, D.S. OrthoMCL: Identification of ortholog groups for eukaryotic genomes. Genome Res., 2003, 13(9), 2178-2189.
[http://dx.doi.org/10.1101/gr.1224503] [PMID: 12952885]
[15]
Emms, D.M.; Kelly, S. OrthoFinder: Phylogenetic orthology inference for comparative genomics. Genome Biol., 2019, 20(1), 238.
[http://dx.doi.org/10.1186/s13059-019-1832-y] [PMID: 31727128]
[16]
Wang, Y.; Coleman-Derr, D.; Chen, G.; Gu, Y.Q. OrthoVenn: A web server for genome wide comparison and annotation of orthologous clusters across multiple species. Nucleic Acids Res., 2015, 43(W1), W78-84.
[http://dx.doi.org/10.1093/nar/gkv487] [PMID: 25964301]
[17]
Gilson, M.K.; Liu, T.; Baitaluk, M.; Nicola, G.; Hwang, L.; Chong, J. BindingDB in 2015: A public database for medicinal chemistry, computational chemistry and systems pharmacology. Nucleic Acids Res., 2016, 44(D1), D1045-D1053.
[http://dx.doi.org/10.1093/nar/gkv1072] [PMID: 26481362]
[18]
Altschul, S.F.; Gish, W.; Miller, W.; Myers, E.W.; Lipman, D.J. Basic local alignment search tool. J. Mol. Biol., 1990, 215(3), 403-410.
[http://dx.doi.org/10.1016/S0022-2836(05)80360-2] [PMID: 2231712]
[19]
Agarwal, S.; Anand, G.; Sharma, S.; Parimita Rath, P.; Gourinath, S.; Bhattacharya, A. EhP3, a homolog of 14-3-3 family of protein partic-ipates in actin reorganization and phagocytosis in Entamoeba histolytica. PLoS Pathog., 2019, 15(5), e1007789.
[http://dx.doi.org/10.1371/journal.ppat.1007789] [PMID: 31095644]
[20]
Paludo, G.P.; Lorenzatto, K.R.; Bonatto, D.; Ferreira, H.B. Systems biology approach reveals possible evolutionarily conserved moon-lighting functions for enolase. Comput. Biol. Chem., 2015, 58, 1-8.
[http://dx.doi.org/10.1016/j.compbiolchem.2015.04.010] [PMID: 25978602]
[21]
Olivares-Illana, V.; Pérez-Montfort, R.; López-Calahorra, F.; Costas, M.; Rodríguez-Romero, A.; Tuena de Gómez-Puyou, M.; Gómez Puyou, A. Structural differences in triosephosphate isomerase from different species and discovery of a multitrypanosomatid inhibitor. Biochemistry, 2006, 45(8), 2556-2560.
[http://dx.doi.org/10.1021/bi0522293] [PMID: 16489748]
[22]
Oliver, D.; Ji, H.; Liu, P.; Gasparian, A.; Gardiner, E.; Lee, S.; Zenteno, A.; Perinskaya, L.O.; Chen, M.; Buckhaults, P.; Broude, E.; Wyatt, M.D.; Valafar, H.; Peña, E.; Shtutman, M. Identification of novel cancer therapeutic targets using a designed and pooled shRNA library screen. Sci. Rep., 2017, 7(1), 43023.
[http://dx.doi.org/10.1038/srep43023] [PMID: 28223711]
[23]
Faria, J.; Loureiro, I.; Santarém, N.; Cecílio, P.; Macedo-Ribeiro, S.; Tavares, J.; Cordeiro-da-Silva, A. Disclosing the essentiality of ribose-5-phosphate isomerase B in Trypanosomatids. Sci. Rep., 2016, 6(1), 26937.
[http://dx.doi.org/10.1038/srep26937] [PMID: 27230471]
[24]
Strzalka, W.; Ziemienowicz, A. Proliferating cell nuclear antigen (PCNA): A key factor in DNA replication and cell cycle regulation. Ann. Bot. (Lond.), 2011, 107(7), 1127-1140.
[http://dx.doi.org/10.1093/aob/mcq243] [PMID: 21169293]
[25]
Hochscherf, J.; Lindenblatt, D.; Witulski, B.; Birus, R.; Aichele, D.; Marminon, C.; Bouaziz, Z.; Le Borgne, M.; Jose, J.; Niefind, K. Unexpected binding mode of a potent indeno[1,2-b]indole-type inhibitor of protein kinase CK2 revealed by complex structures with the catalytic subunit CK2α and its paralog CK2α′. Pharmaceuticals (Basel), 2017, 10(4), 98.
[http://dx.doi.org/10.3390/ph10040098] [PMID: 29236079]
[26]
Zhang, W.; Sviripa, V.; Chen, X.; Shi, J.; Yu, T.; Hamza, A.; Ward, N.D.; Kril, L.M.; Vander Kooi, C.W.; Zhan, C.G.; Evers, B.M.; Watt, D.S.; Liu, C.; Fluorinated, N. N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. ACS Chem. Biol., 2013, 8(4), 796-803.
[http://dx.doi.org/10.1021/cb3005353] [PMID: 23363077]
[27]
Cordeiro, A.T. NADPH producing enzymes as promising drug targets for Chagas disease. Curr. Med. Chem., 2019, 26(36), 6564-6571.
[http://dx.doi.org/10.2174/0929867325666181009152844] [PMID: 30306853]
[28]
Olin-Sandoval, V.; Moreno-Sánchez, R.; Saavedra, E. Targeting trypanothione metabolism in trypanosomatid human parasites. Curr. Drug Targets, 2010, 11(12), 1614-1630.
[http://dx.doi.org/10.2174/1389450111009011614] [PMID: 20735352]
[29]
Giordana, L.; Sosa, M.H.; Leroux, A.E.; Mendoza, E.F.R.; Petray, P.; Nowicki, C. Molecular and functional characterization of two malic enzymes from Leishmania parasites. Mol. Biochem. Parasitol., 2018, 219, 67-76.
[http://dx.doi.org/10.1016/j.molbiopara.2017.11.001] [PMID: 29128656]
[30]
de A S Navarro, M.V.; Gomes Dias, S.M.; Mello, L.V.; da Silva Giotto, M.T.; Gavalda, S.; Blonski, C.; Garratt, R.C.; Rigden, D.J. Structural flexibility in Trypanosoma brucei enolase revealed by X-ray crystallography and molecular dynamics. FEBS J., 2007, 274(19), 5077-5089.
[http://dx.doi.org/10.1111/j.1742-4658.2007.06027.x] [PMID: 17822439]
[31]
Wang, L.; Qu, M.; Huang, S.; Fu, Y.; Yang, L.; He, S.; Li, L.; Zhang, Z.; Lin, Q.; Zhang, L. A novel α-enolase-targeted drug delivery system for high efficacy prostate cancer therapy. Nanoscale, 2018, 10(28), 13673-13683.
[http://dx.doi.org/10.1039/C8NR03297A] [PMID: 29987301]
[32]
Cho, H.; Um, J.; Lee, J.-H.; Kim, W.-H.; Kang, W.S.; Kim, S.H.; Ha, H.H.; Kim, Y.C.; Ahn, Y.K.; Jung, D.W.; Williams, D.R. ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes. Sci. Rep., 2017, 7(1), 44186.
[http://dx.doi.org/10.1038/srep44186] [PMID: 28272459]
[33]
Wescott, H.H.; Zuniga, E.S.; Bajpai, A.; Trujillo, C.; Ehrt, S.; Schnappinger, D.; Roberts, D.M.; Parish, T. Identification of enolase as the target of 2-aminothiazoles in Mycobacterium tuberculosis. Front. Microbiol., 2018, 9, 2542.
[http://dx.doi.org/10.3389/fmicb.2018.02542] [PMID: 30416491]
[34]
Wang, Z.; Wang, Y.; Zhu, S.; Liu, Y.; Peng, X.; Zhang, S.; Zhang, Z.; Qiu, Y.; Jin, M.; Wang, R.; Zhong, Y.; Kong, D. DT-13 inhibits proliferation and metastasis of human prostate cancer cells through blocking PI3K/Akt pathway. Front. Pharmacol., 2018, 9, 1450.
[http://dx.doi.org/10.3389/fphar.2018.01450] [PMID: 30581390]
[35]
Lam, T.G.; Jeong, Y.S.; Kim, S.A.; Ahn, S.G. New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways. Cancer Sci., 2018, 109(3), 699-709.
[http://dx.doi.org/10.1111/cas.13482] [PMID: 29285837]
[36]
Xiong, T.; Li, Z.; Huang, X.; Lu, K.; Xie, W.; Zhou, Z.; Tu, J. TO901317 inhibits the development of hepatocellular carcinoma by LXRα/Glut1 decreasing glycometabolism. Am. J. Physiol. Gastrointest. Liver Physiol., 2019, 316(5), G598-G607.
[http://dx.doi.org/10.1152/ajpgi.00061.2018] [PMID: 30817182]
[37]
Bartolowits, M.D.; Gast, J.M.; Hasler, A.J.; Cirrincione, A.M.; O’Connor, R.J.; Mahmoud, A.H.; Lill, M.A.; Davisson, V.J. Discovery of inhibitors for proliferating cell nuclear antigen using a computational-based linked-multiple-fragment screen. ACS Omega, 2019, 4(12), 15181-15196.
[http://dx.doi.org/10.1021/acsomega.9b02079] [PMID: 31552364]
[38]
Cardona-Felix, C.S.; Lara-Gonzalez, S.; Brieba, L.G. Structure and biochemical characterization of proliferating cellular nuclear antigen from a parasitic protozoon. Acta Crystallogr. D Biol. Crystallogr., 2011, 67(Pt 6), 497-505.
[http://dx.doi.org/10.1107/S0907444911010547] [PMID: 21636889]
[39]
De Lima, A.R.; Noris-Suárez, K.; Bretaña, A.; Contreras, V.T.; Navarro, M.C.; Pérez-Ybarra, L.; Bubis, J. Growth arrest and morphological changes triggered by emodin on Trypanosoma cruzi epimastigotes cultivated in axenic medium. Biochimie, 2017, 142, 31-40.
[http://dx.doi.org/10.1016/j.biochi.2017.08.005] [PMID: 28803999]
[40]
Bestgen, B.; Krimm, I.; Kufareva, I.; Kamal, A.A.M.; Seetoh, W-G.; Abell, C.; Hartmann, R.W.; Abagyan, R.; Cochet, C.; Le Borgne, M.; Engel, M.; Lomberget, T. 2-Aminothiazole derivatives as selective allosteric modulators of the protein kinase CK2. 1. Identification of an allosteric binding site. J. Med. Chem., 2019, 62(4), 1803-1816.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01766] [PMID: 30689953]
[41]
Loureiro, I.; Faria, J.; Clayton, C.; Macedo-Ribeiro, S.; Santarém, N.; Roy, N.; Cordeiro-da-Siva, A.; Tavares, J. Ribose 5-phosphate isomerase B knockdown compromises Trypanosoma brucei bloodstream form infectivity. PLoS Negl. Trop. Dis., 2015, 9(1), e3430.
[http://dx.doi.org/10.1371/journal.pntd.0003430] [PMID: 25568941]
[42]
Stern, A.L.; Naworyta, A.; Cazzulo, J.J.; Mowbray, S.L. Structures of type B ribose 5-phosphate isomerase from Trypanosoma cruzi shed light on the determinants of sugar specificity in the structural family. FEBS J., 2011, 278(5), 793-808.
[http://dx.doi.org/10.1111/j.1742-4658.2010.07999.x] [PMID: 21205211]
[43]
Enriquez-Flores, S.; Rodriguez-Romero, A.; Hernandez-Alcantara, G.; De la Mora-De la Mora, I.; Gutierrez-Castrellon, P.; Carvajal, K.; Lopez-Velazquez, G.; Reyes-Vivas, H. Species-specific inhibition of Giardia lamblia triosephosphate isomerase by localized perturbation of the homodimer. Mol. Biochem. Parasitol., 2008, 157(2), 179-186.
[http://dx.doi.org/10.1016/j.molbiopara.2007.10.013] [PMID: 18077010]
[44]
Minini, L.; Álvarez, G.; González, M.; Cerecetto, H.; Merlino, A. Molecular docking and molecular dynamics simulation studies of Trypanosoma cruzi triosephosphate isomerase inhibitors. Insights into the inhibition mechanism and selectivity. J. Mol. Graph. Model., 2015, 58, 40-49.
[http://dx.doi.org/10.1016/j.jmgm.2015.02.002] [PMID: 25829097]
[45]
Velázquez-López, J.M.; Hernández-Campos, A.; Yépez-Mulia, L.; Téllez-Valencia, A.; Flores-Carrillo, P.; Nieto-Meneses, R.; Castillo, R. Synthesis and trypanocidal activity of novel benzimidazole derivatives. Bioorg. Med. Chem. Lett., 2016, 26(17), 4377-4381.
[http://dx.doi.org/10.1016/j.bmcl.2015.08.018] [PMID: 27503677]
[46]
Reyes-Vivas, H.; de la Mora-de la Mora, I.; Castillo-Villanueva, A.; Yépez-Mulia, L.; Hernández-Alcántara, G.; Figueroa-Salazar, R.; García-Torres, I.; Gómez-Manzo, S.; Méndez, S.T.; Vanoye-Carlo, A.; Marcial-Quino, J.; Torres-Arroyo, A.; Oria-Hernández, J.; Gutiérrez-Castrellón, P.; Enríquez-Flores, S.; López-Velázquez, G. Giardial triosephosphate isomerase as possible target of the cytotoxic effect of omeprazole in Giardia lamblia. Antimicrob. Agents Chemother., 2014, 58(12), 7072-7082.
[http://dx.doi.org/10.1128/AAC.02900-14] [PMID: 25223993]
[47]
García-Torres, I.; de la Mora-de la Mora, I.; Marcial-Quino, J.; Gómez-Manzo, S.; Vanoye-Carlo, A.; Navarrete-Vázquez, G.; Colín-Lozano, B.; Gutiérrez-Castrellón, P.; Sierra-Palacios, E.; López-Velázquez, G.; Enríquez-Flores, S. Proton pump inhibitors drastically modify triosephosphate isomerase from Giardia lamblia at functional and structural levels, providing molecular leads in the design of new antigiardiasic drugs. Biochim. Biophys. Acta, 2016, 1860(1 Pt A), 97-107.
[http://dx.doi.org/10.1016/j.bbagen.2015.10.021] [PMID: 26518348]

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