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Targeting HDACs of apicomplexans: structural insights for a better treatment

Published online by Cambridge University Press:  31 March 2022

Caroline de Moraes de Siqueira ,
Mariana Sayuri Ishikawa Fragoso ,
Vanessa Rossini Severo ,
Isis Venturi Biembengut ,
Sheila Cristina Nardelli  and
Tatiana de Arruda Campos Brasil de Souza Open the ORCID record for Tatiana de Arruda Campos Brasil de Souza [Opens in a new window]
Caroline de Moraes de Siqueira
Affiliation:
Instituto Carlos Chagas – Fundação Oswaldo Cruz – Fiocruz/PR, Curitiba, PR, Brazil
Mariana Sayuri Ishikawa Fragoso
Affiliation:
Instituto Carlos Chagas – Fundação Oswaldo Cruz – Fiocruz/PR, Curitiba, PR, Brazil
Vanessa Rossini Severo
Affiliation:
Instituto Carlos Chagas – Fundação Oswaldo Cruz – Fiocruz/PR, Curitiba, PR, Brazil
Isis Venturi Biembengut
Affiliation:
Instituto Carlos Chagas – Fundação Oswaldo Cruz – Fiocruz/PR, Curitiba, PR, Brazil
Sheila Cristina Nardelli
Affiliation:
Instituto Carlos Chagas – Fundação Oswaldo Cruz – Fiocruz/PR, Curitiba, PR, Brazil
Tatiana de Arruda Campos Brasil de Souza*
Affiliation:
Instituto Carlos Chagas – Fundação Oswaldo Cruz – Fiocruz/PR, Curitiba, PR, Brazil
*
Author for correspondence: Tatiana de Arruda Campos Brasil de Souza, E-mail: [email protected]
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Abstract

Aetiologic agents of diseases such as malaria and toxoplasmosis are found in representatives of the phylum Apicomplexa. Therefore, apicomplexan parasites are known to have a significant impact on public health. Epigenetic factors such as histone acetylation/deacetylation are among the main mechanisms of gene regulation in these parasites. Histone deacetylases (HDACs) have aroused a great deal of interest over the past 20 years for being promising targets in the development of drugs for treating several diseases such as cancer. In addition, they have also been shown to be effective for parasitic diseases. However, little is known about the structure of these proteins, as well as their interactions with specific ligands. In this paper, we modelled 14 HDACs from different apicomplexan parasites and performed molecular docking with 12 ligands analogous to the HDAC inhibitors FR235222 and apicidin, which had previously been tested against Toxoplasma gondii and Plasmodium falciparum. In this in silico study, we were able to gather relevant structural data regarding these proteins as well as insights into protein–ligand interactions for testing and developing drugs for these diseases.

Keywords

ApicidinApicomplexaHDAC inhibitorHDACshomology modellingmolecular docking
Type
Research Article
Information
Parasitology , Volume 149 , Issue 7 , June 2022 , pp. 956 - 967
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Copyright
Copyright © The Author(s), 2022. Published by Cambridge University Press

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References

Abraham, MJ, Murtola, T, Schulz, R, Páll, S, Smith, JC, Hess, B and Lindahl, E (2015) GROMACS: high performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX 1–2, 19–25.CrossRefGoogle Scholar
Anandakrishnan, R, Aguilar, B and Onufriev, AV (2012) H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. Nucleic Acids Research 40, W537–W541.10.1093/nar/gks375CrossRefGoogle ScholarPubMed
Anderson, RJ, Weng, Z, Campbell, RK and Jiang, X (2005) Main-chain conformational tendencies of amino acids. Proteins 60, 679–689.CrossRefGoogle ScholarPubMed
Andrews, KT, Gupta, AP, Tran, TN, Fairlie, DP, Gobert, GN and Bozdech, Z (2012) Comparative gene expression profiling of P. falciparum malaria parasites exposed to three different histone deacetylase inhibitors. PLoS One 7, e31847.CrossRefGoogle ScholarPubMed
Balaji, S (2005) Discovery of the principal specific transcription factors of Apicomplexa and their implication for the evolution of the AP2-integrase DNA binding domains. Nucleic Acids Research 33, 3994–4006.CrossRefGoogle ScholarPubMed
Ballante, F, Reddy, DR, Zhou, NJ and Marshall, GL (2017) Structural insights of SmKDAC8 inhibitors: targeting Schistosoma epigenetics through a combined structure-based 3D QSAR, in vitro and synthesis strategy. Bioorganic & Medicinal Chemistry 25, 2105–2132.10.1016/j.bmc.2017.02.020CrossRefGoogle ScholarPubMed
Benedetti, R, Conte, M and Altucci, L (2015) Targeting histone deacetylases in diseases: where are we? Antioxidants & Redox Signaling 23, 99–126.10.1089/ars.2013.5776CrossRefGoogle Scholar
Bougdour, A, Maubon, D, Baldacci, P, Ortet, P, Bastien, O, Bouillon, A, Barale, J-C, Pelloux, H, Ménard, R and Hakimi, M-A (2009) Drug inhibition of HDAC3 and epigenetic control of differentiation in Apicomplexa parasites. The Journal of Experimental Medicine 206, 953–966.10.1084/jem.20082826CrossRefGoogle ScholarPubMed
Bussi, G, Donadio, D and Parrinello, M (2007) Canonical sampling through velocity rescaling. The Journal of Chemical Physics 126, 014101.10.1063/1.2408420CrossRefGoogle ScholarPubMed
Chaal, BK, Gupta, AP, Wastuwidyaningtyas, BD, Luah, Y-H and Bozdech, Z (2010) Histone deacetylases play a major role in the transcriptional regulation of the Plasmodium falciparum life cycle. PLoS Pathogens 6, e1000737.CrossRefGoogle Scholar
Chahal, V, Nirwan, S and Kakkar, R (2020) Combined approach of homology modeling, molecular dynamics, and docking: computer-aided drug discovery. In Ramasami, P (ed.), Computational Chemistry Methods: Applications, Vol. 4. Berlin, Boston: De Gruyter, pp. 63–88. https://doi.org/10.1515/9783110631623-005.CrossRefGoogle Scholar
Chua, MJ, Arnold, MSJ, Xu, W, Lancelot, J, Lamotte, S, Späth, GF, Prina, E, Pierce, RJ, Fairlie, DP, Skinner-Adams, TS and Andrews, KT (2017) Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth. International Journal for Parasitology: Drugs and Drug Resistance 7, 42–50.Google ScholarPubMed
Colletti, SL, Myers, RW, Darkin-Rattray, SJ, Gurnett, AM, Dulski, PM, Galuska, S, Allocco, JJ, Ayer, MB, Li, C, Lim, J, Crumley, TM, Cannova, C, Schmatz, DM, Wyvratt, MJ, Fisher, MH and Meinke, PT (2001) Broad spectrum antiprotozoal agents that inhibit histone deacetylase: structure–activity relationships of apicidin. Part 2. Bioorganic & Medicinal Chemistry Letters 11, 113–117.10.1016/S0960-894X(00)00605-3CrossRefGoogle ScholarPubMed
Darkin-Rattray, SJ, Gurnett, AM, Myers, RW, Dulski, PM, Crumley, TM, Allocco, JJ, Cannova, C, Meinke, PT, Colletti, SL, Bednarek, MA, Singh, SB, Goetz, MA, Dombrowski, AW, Polishook, JD and Schmatz, DM (1996) Apicidin: a novel antiprotozoal agent that inhibits parasite histone deacetylase. Proceedings of the National Academy of Sciences of the United States of America 93, 13143–13147.CrossRefGoogle ScholarPubMed
Di Micco, S, Terracciano, S, Bruno, I, Rodriquez, M, Riccio, R, Taddei, M and Bifulco, G (2008) Molecular modeling studies toward the structural optimization of new cyclopeptide-based HDAC inhibitors modeled on the natural product FR235222. Bioorganic & Medicinal Chemistry 16, 8635–8642.CrossRefGoogle ScholarPubMed
Dunay, IR, Gajurel, K, Dhakal, R, Liesenfeld, O and Montoya, JG (2018) Treatment of toxoplasmosis: historical perspective, animal models, and current clinical practice. Clinical Microbiology Reviews 31. doi: 10.1128/CMR.00057-17.CrossRefGoogle ScholarPubMed
Engel, JA, Jones, AJ, Avery, VM, Sumanadasa, SDM, Ng, SS, Fairlie, DP, Skinner-Adams, T and Andrews, KT (2015) Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodium and Trypanosoma parasites. International Journal for Parasitology: Drugs and Drug Resistance 5, 117–126.Google ScholarPubMed
Essmann, U, Perera, L, Berkowitz, ML, Darden, T, Lee, H and Pedersen, LG (1995) A smooth particle mesh Ewald method. The Journal of Chemical Physics 103, 8577–8593.CrossRefGoogle Scholar
Frénal, K, Dubremetz, J-F, Lebrun, M and Soldati-Favre, D (2017) Gliding motility powers invasion and egress in Apicomplexa. Nature Reviews. Microbiology 15, 645–660.10.1038/nrmicro.2017.86CrossRefGoogle ScholarPubMed
Guidi, A, Saccoccia, F, Gennari, N, Gimmelli, R, Nizi, E, Lalli, C, Paonessa, G, Papoff, G, Bresciani, A and Ruberti, G (2018) Identification of novel multi-stage histone deacetylase (HDAC) inhibitors that impair Schistosoma mansoni viability and egg production. Parasites & Vectors 11, 668.10.1186/s13071-018-3268-8CrossRefGoogle ScholarPubMed
Haug, EJ, Arora, JS and Matsui, K (1976) A steepest-descent method for optimization of mechanical systems. Journal of Optimization Theory and Applications 19, 401–424.CrossRefGoogle Scholar
Huang, J, Rauscher, S, Nawrocki, G, Ran, T, Feig, M, de Groot, BL, Grubmüller, H and Grubmüller, AD, Jr. (2017) HARMM36m: An improved force field for folded and intrinsically disordered proteins. Nature Methods 14, 71–73.10.1038/nmeth.4067CrossRefGoogle Scholar
Inoue, A and Fujimoto, D (1969) Enzymatic deacetylation of histone. Biochemical and Biophysical Research Communications 36, 146–150.10.1016/0006-291X(69)90661-5CrossRefGoogle ScholarPubMed
Iwanaga, S, Kaneko, I, Kato, T and Yuda, M (2012) Identification of an AP2-family protein that is critical for malaria liver stage development. PLoS One 7, e47557.10.1371/journal.pone.0047557CrossRefGoogle ScholarPubMed
Jeninga, M, Quinn, J and Petter, M (2019) ApiAP2 transcription factors in apicomplexan parasites. Pathogens (Basel, Switzerland) 8, 47.Google ScholarPubMed
Jorgensen, WL, Chandrasekhar, J, Madura, JD, Impey, RW and Klein, ML (1983) Comparison of simple potential functions for simulating liquid water. The Journal of Chemical Physics 79, 926–935.CrossRefGoogle Scholar
Joshi, MB, Lin, DT, Chiang, PH, Goldman, ND, Fujioka, H, Aikawa, M and Syin, C (1999) Molecular cloning and nuclear localization of a histone deacetylase homologue in Plasmodium falciparum. Molecular and Biochemical Parasitology 99, 11–19.CrossRefGoogle ScholarPubMed
Kumar, A, Dhar, SK and Subbarao, N (2018). In silico identification of inhibitors against Plasmodium falciparum histone deacetylase 1 (PfHDAC-1). Journal of Molecular Modeling 24, 232.CrossRefGoogle Scholar
Laskowski, RA, Jabłońska, J, Pravda, L, Vařeková, RS and Thornton, JM (2018) PDBsum: structural summaries of PDB entries. Protein Science 27, 129–134.CrossRefGoogle ScholarPubMed
Lee, J-H, Bollschweiler, D, Schäfer, T and Huber, R (2021) Structural basis for the regulation of nucleosome recognition and HDAC activity by histone deacetylase assemblies. Science Advances 7, eabd4413.CrossRefGoogle ScholarPubMed
Melesina, J, Robaa, D, Pierce, RJ, Romier, C and Sippl, W (2015) Homology modeling of parasite histone deacetylases to guide the structure-based design of selective inhibitors. Journal of Molecular Graphics & Modelling 62, 342–361.CrossRefGoogle ScholarPubMed
Miller, TA, Witter, DJ and Belvedere, S (2003) Histone deacetylase inhibitors. Journal of Medicinal Chemistry 46, 5097–5116.CrossRefGoogle ScholarPubMed
Mori, H, Urano, Y, Abe, F, Furukawa, S, Furukawa, S, Tsurumi, Y, Sakamoto, K, Hashimoto, M, Takase, S, Hino, M and Fujii, T (2003) FR235222, a fungal metabolite, is a novel immunosuppressant that inhibits mammalian histone deacetylase (HDAC). I. Taxonomy, fermentation, isolation and biological activities. The Journal of Antibiotics 56, 72–79.10.7164/antibiotics.56.72CrossRefGoogle ScholarPubMed
Morrison, DA (2009) Evolution of the Apicomplexa: where are we now? Trends in Parasitology 25, 375–382.CrossRefGoogle ScholarPubMed
Nardelli, SC, Che, F-Y, de Monerri, S, Xiao, NC, Nieves, H, Madrid-Aliste, E, Angel, C, Sullivan, SO, Angeletti, WJ, Kim, RH, and Weiss, K and M, L (2013) The histone code of Toxoplasma gondii comprises conserved and unique posttranslational modifications. mBio 4. doi: 10.1128/mBio.00922-13.CrossRefGoogle ScholarPubMed
Oberstaller, J, Pumpalova, Y, Schieler, A, Llinás, M and Kissinger, JC (2014) The Cryptosporidium parvum ApiAP2 gene family: insights into the evolution of apicomplexan AP2 regulatory systems. Nucleic Acids Research 42, 8271–8284.CrossRefGoogle ScholarPubMed
Painter, HJ, Campbell, TL and Llinás, M (2011) The apicomplexan AP2 family: integral factors regulating Plasmodium development. Molecular and Biochemical Parasitology 176, 1–7.CrossRefGoogle ScholarPubMed
Pettersen, EF, Goddard, TD, Huang, CC, Couch, GS, Greenblatt, DM, Meng, EC and Ferrin, TE (2004) UCSF Chimera – a visualization system for exploratory research and analysis. Journal of Computational Chemistry 25, 1605–1612.CrossRefGoogle ScholarPubMed
Radke, JR, Behnke, MS, Mackey, AJ, Radke, JB, Roos, DS and White, MW (2005) The transcriptome of Toxoplasma gondii. BMC Biology 3, 26.CrossRefGoogle ScholarPubMed
Ramaprasad, A, Mourier, T, Naeem, R, Malas, TB, Moussa, E, Panigrahi, A, Vermont, SJ, Otto, TD, Wastling, J and Pain, A (2015) Comprehensive evaluation of Toxoplasma gondii VEG and Neospora caninum LIV genomes with tachyzoite stage transcriptome and proteome defines novel transcript features. PLoS One 10, e0124473.CrossRefGoogle ScholarPubMed
Sánchez, R and Sali, A (1997) Advances in comparative protein-structure modelling. Current Opinion in Structural Biology 7, 206–214.CrossRefGoogle ScholarPubMed
Sepehri, Z, Beacon, TH, Osman, FDS, Jahan, S and Davie, JR (2019) DNA methylation and chromatin modifications. In Nutritional Epigenomics. United States: Elsevier, pp. 13–36. doi: 10.1016/B978-0-12-816843-1.00002-3.CrossRefGoogle Scholar
Seto, E and Yoshida, M (2014) Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harbor Perspectives in Biology 6, a018713.CrossRefGoogle ScholarPubMed
Sippl, MJ (1993) Recognition of errors in three-dimensional structures of proteins. Proteins 17, 355–362.CrossRefGoogle ScholarPubMed
Söding, J, Biegert, A and Lupas, AN (2005) The HHpred interactive server for protein homology detection and structure prediction. Nucleic Acids Research 33, W244–W248.10.1093/nar/gki408CrossRefGoogle ScholarPubMed
Srivastava, S, White, MW and Sullivan, WJ (2020) Toxoplasma gondii AP2XII-2 contributes to proper progression through S-phase of the cell cycle. mSphere 5. doi: 10.1128/mSphere.00542-20.CrossRefGoogle ScholarPubMed
Terui, Y, Chu, Y, Li, J, Ando, T, Fukunaga, T, Aoki, T and Toda, Y (2008) New cyclic tetrapeptides from Nonomuraea sp. TA-0426 that inhibit glycine transporter type 1 (GlyT1). Bioorganic & Medicinal Chemistry Letters 18, 6321–6323.10.1016/j.bmcl.2008.10.104CrossRefGoogle Scholar
Trott, O and Olson, AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry 31, 455–461.Google ScholarPubMed
Vaca, HR, Celentano, AM, Toscanini, MA, Heimburg, T, Ghazy, E, Zeyen, P, Hauser, A-T, Oliveira, G, Elissondo, MC, Jung, M, Sippl, W, Camicia, F and Rosenzvit, MC (2021) The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs. PLoS Neglected Tropical Diseases 15, e0009226.CrossRefGoogle ScholarPubMed
Verdin, E and Ott, M (2015) 50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond. Nature Reviews. Molecular Cell Biology 16, 258–264.CrossRefGoogle ScholarPubMed
Webb, B and Sali, A (2016) Comparative protein structure modeling using MODELLER. Current Protocols in Bioinformatics 54, 5.6.1–5.6.37.CrossRefGoogle ScholarPubMed
WHO Guidelines Approved by the Guidelines Review Committee (2015) Guidelines for the Treatment of Malaria, 3rd Edn, Geneva: World Health Organization.Google Scholar
Wiederstein, M and Sippl, MJ (2007) ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Research 35, W407–W410.CrossRefGoogle ScholarPubMed
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