Inhibition of Hemoglobin Degrading Protease Falcipain-2 as a Mechanism for Anti-Malarial Activity of Triazole-Amino Acid Hybrids

Author(s): Vigyasa Singh, Rahul Singh Hada, Amad Uddin, Babita Aneja, Mohammad Abid, Kailash C. Pandey, Shailja Singh*

Journal Name: Current Topics in Medicinal Chemistry

Volume 20 , Issue 5 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Novel drug development against malaria parasite over old conventional antimalarial drugs is essential due to rapid and indiscriminate use of drugs, which led to the emergence of resistant strains.

Methods: In this study, previously reported triazole-amino acid hybrids (13-18) are explored against Plasmodium falciparum as antimalarial agents. Among six compounds, 15 and 18 exhibited antimalarial activity against P. falciparum with insignificant hemolytic activity and cytotoxicity towards HepG2 mammalian cells. In molecular docking studies, both compounds bind into the active site of PfFP-2 and block its accessibility to the substrate that leads to the inhibition of target protein further supported by in vitro analysis.

Results: Antimalarial half-maximal inhibitory concentration (IC50) of 15 and 18 compounds were found to be 9.26 μM and 20.62 μM, respectively. Blood stage specific studies showed that compounds, 15 and 18 are effective at late trophozoite stage and block egress pathway of parasites. Decreased level of free monomeric heme was found in a dose dependent manner after the treatment with compounds 15 and 18, which was further evidenced by the reduction in percent of hemoglobin hydrolysis. Compounds 15 and 18 hindered hemoglobin degradation via intra- and extracellular cysteine protease falcipain-2 (PfFP-2) inhibitory activity both in in vitro and in vivo in P. falciparum.

Conclusion: We report antimalarial potential of triazole-amino acid hybrids and their role in the inhibition of cysteine protease PfFP-2 as its mechanistic aspect.

Keywords: Plasmodium falciparum, Cysteine protease, Falcipain-2, Hemoglobin degradation, In-vivo protease activity, Triazole- amino acid hybrids.

[1]
Hunt, N.H.; Golenser, J.; Chan-Ling, T.; Parekh, S.; Rae, C.; Potter, S.; Medana, I.M.; Miu, J.; Ball, H.J. Immunopathogenesis of cerebral malaria. Int. J. Parasitol., 2006, 36(5), 569-582.
[http://dx.doi.org/10.1016/j.ijpara.2006.02.016] [PMID: 16678181]
[2]
Walker, E.J.; Peterson, G.M.; Grech, J.; Paragalli, E.; Thomas, J. Are we doing enough to prevent poor-quality antimalarial medicines in the developing world? BMC Public Health, 2018, 18(1), 630.
[http://dx.doi.org/10.1186/s12889-018-5521-7] [PMID: 29764407 ]
[3]
Rich, S.M.; Leendertz, F.H.; Xu, G.; LeBreton, M.; Djoko, C.F.; Aminake, M.N.; Takang, E.E.; Diffo, J.L.; Pike, B.L.; Rosenthal, B.M.; Formenty, P.; Boesch, C.; Ayala, F.J.; Wolfe, N.D. The origin of malignant malaria. Proc. Natl. Acad. Sci. USA, 2009, 106(35), 14902-14907.
[http://dx.doi.org/10.1073/pnas.0907740106] [PMID: 19666593]
[4]
Antony, H.A.; Parija, S.C. Antimalarial drug resistance: An overview. Trop. Parasitol., 2016, 6(1), 30-41.
[http://dx.doi.org/10.4103/2229-5070.175081] [PMID: 26998432]
[5]
Thu, A.M.; Phyo, A.P.; Landier, J.; Parker, D.M.; Nosten, F.H. Combating multidrug-resistant Plasmodium falciparum malaria. FEBS J., 2017, 284(16), 2569-2578.
[http://dx.doi.org/10.1111/febs.14127] [PMID: 28580606 ]
[6]
Ettari, R.; Zappalà, M.; Micale, N.; Schirmeister, T.; Gelhaus, C.; Leippe, M.; Evers, A.; Grasso, S. Synthesis of novel peptidomimetics as inhibitors of protozoan cysteine proteases falcipain-2 and rhodesain. Eur. J. Med. Chem., 2010, 45(7), 3228-3233.
[http://dx.doi.org/10.1016/j.ejmech.2010.04.003] [PMID: 20434817]
[7]
Rosenthal, P.J. Falcipains and other cysteine proteases of malaria parasites. Adv. Exp. Med. Biol., 2011, 712, 30-48.
[http://dx.doi.org/10.1007/978-1-4419-8414-2_3] [PMID: 21660657]
[8]
Lehmann, C.; Heitmann, A.; Mishra, S.; Burda, P.C.; Singer, M.; Prado, M.; Niklaus, L.; Lacroix, C.; Ménard, R.; Frischknecht, F.; Stanway, R.; Sinnis, P.; Heussler, V. A cysteine protease inhibitor of plasmodium berghei is essential for exo-erythrocytic development. PLoS Pathog., 2014, 10(8) e1004336
[http://dx.doi.org/10.1371/journal.ppat.1004336] [PMID: 25166051]
[9]
Melo, P.M.S.; El Chamy Maluf, S.; Azevedo, M.F.; Paschoalin, T.; Budu, A.; Bagnaresi, P.; Henrique-Silva, F.; Soares-Costa, A.; Gazarini, M.L.; Carmona, A.K. Inhibition of Plasmodium falciparum cysteine proteases by the sugarcane cystatin CaneCPI-4. Parasitol. Int., 2018, 67(2), 233-236.
[http://dx.doi.org/10.1016/j.parint.2017.12.005] [PMID: 29288140 ]
[10]
Heussler, V.; Rennenberg, A.; Stanway, R. Host cell death induced by the egress of intracellular Plasmodium parasites. Apoptosis, 2010, 15(3), 376-385.
[http://dx.doi.org/10.1007/s10495-009-0435-6] [PMID: 20012364]
[11]
Aly, A.S.; Matuschewski, K. A malarial cysteine protease is necessary for Plasmodium sporozoite egress from oocysts. J. Exp. Med., 2005, 202(2), 225-230.
[http://dx.doi.org/10.1084/jem.20050545] [PMID: 16027235]
[12]
Korde, R.; Bhardwaj, A.; Singh, R.; Srivastava, A.; Chauhan, V.S.; Bhatnagar, R.K.; Malhotra, P. A prodomain peptide of Plasmodium falciparum cysteine protease (falcipain-2) inhibits malaria parasite development. J. Med. Chem., 2008, 51(11), 3116-3123.
[http://dx.doi.org/10.1021/jm070735f] [PMID: 18461922 ]
[13]
Chakka, S.K.; Kalamuddin, M.; Sundararaman, S.; Wei, L.; Mundra, S.; Mahesh, R.; Malhotra, P.; Mohmmed, A.; Kotra, L.P. Identification of novel class of falcipain-2 inhibitors as potential antimalarial agents. Bioorg. Med. Chem., 2015, 23(9), 2221-2240.
[http://dx.doi.org/10.1016/j.bmc.2015.02.062] [PMID: 25840796]
[14]
Dhawan, S.; Dua, M.; Chishti, A.H.; Hanspal, M. Ankyrin peptide blocks falcipain-2-mediated malaria parasite release from red blood cells. J. Biol. Chem., 2003, 278(32), 30180-30186.
[http://dx.doi.org/10.1074/jbc.M305132200] [PMID: 12775709 ]
[15]
Dasaradhi, P.V.; Mohmmed, A.; Kumar, A.; Hossain, M.J.; Bhatnagar, R.K.; Chauhan, V.S.; Malhotra, P. A role of falcipain-2, principal cysteine proteases of Plasmodium falciparum in merozoite egression. Biochem. Biophys. Res. Commun., 2005, 336(4), 1062-1068.
[http://dx.doi.org/10.1016/j.bbrc.2005.08.213] [PMID: 16165088]
[16]
Glushakova, S.; Mazar, J.; Hohmann-Marriott, M.F.; Hama, E.; Zimmerberg, J. Irreversible effect of cysteine protease inhibitors on the release of malaria parasites from infected erythrocytes. Cell. Microbiol., 2009, 11(1), 95-105.
[http://dx.doi.org/10.1111/j.1462-5822.2008.01242.x] [PMID: 19016793 ]
[17]
Nizi, E.; Sferrazza, A.; Fabbrini, D.; Nardi, V.; Andreini, M.; Graziani, R.; Gennari, N.; Bresciani, A.; Paonessa, G.; Harper, S. Peptidomimetic nitrile inhibitors of malarial protease falcipain-2 with high selectivity against human cathepsins. Bioorg. Med. Chem. Lett., 2018, 28(9), 1540-1544.
[http://dx.doi.org/10.1016/j.bmcl.2018.03.069] [PMID: 29615344 ]
[18]
Sharma, K.; Shrivastava, A.; Mehra, R.N.; Deora, G.S.; Alam, M.M.; Zaman, M.S.; Akhter, M. Synthesis of novel benzimidazole acrylonitriles for inhibition of Plasmodium falciparum growth by dual target inhibition. Arch. Pharm. (Weinheim), 2018, 351(1)
[http://dx.doi.org/10.1002/ardp.201700251] [PMID: 29227011 ]
[19]
Bhattacharya, A.; Mishra, L.C.; Sharma, M.; Awasthi, S.K.; Bhasin, V.K. Antimalarial pharmacodynamics of chalcone derivatives in combination with artemisinin against Plasmodium falciparum in vitro. Eur. J. Med. Chem., 2009, 44(9), 3388-3393.
[http://dx.doi.org/10.1016/j.ejmech.2009.02.008] [PMID: 19269069]
[20]
Gibbons, P.; Verissimo, E.; Araujo, N.C.; Barton, V.; Nixon, G.L.; Amewu, R.K.; Chadwick, J.; Stocks, P.A.; Biagini, G.A.; Srivastava, A.; Rosenthal, P.J.; Gut, J.; Guedes, R.C.; Moreira, R.; Sharma, R.; Berry, N.; Cristiano, M.L.; Shone, A.E.; Ward, S.A.; O’Neill, P.M. Endoperoxide carbonyl falcipain 2/3 inhibitor hybrids: toward combination chemotherapy of malaria through a single chemical entity. J. Med. Chem., 2010, 53(22), 8202-8206.
[http://dx.doi.org/10.1021/jm1009567] [PMID: 20979352 ]
[21]
Ang, K.K.; Ratnam, J.; Gut, J.; Legac, J.; Hansell, E.; Mackey, Z.B.; Skrzypczynska, K.M.; Debnath, A.; Engel, J.C.; Rosenthal, P.J.; McKerrow, J.H.; Arkin, M.R.; Renslo, A.R. Mining a cathepsin inhibitor library for new antiparasitic drug leads. PLoS Negl. Trop. Dis., 2011, 5(5) e1023
[http://dx.doi.org/10.1371/journal.pntd.0001023] [PMID: 21572521]
[22]
Coterón, J.M.; Catterick, D.; Castro, J.; Chaparro, M.J.; Díaz, B.; Fernández, E.; Ferrer, S.; Gamo, F.J.; Gordo, M.; Gut, J.; de las Heras, L.; Legac, J.; Marco, M.; Miguel, J.; Muñoz, V.; Porras, E.; de la Rosa, J.C.; Ruiz, J.R.; Sandoval, E.; Ventosa, P.; Rosenthal, P.J.; Fiandor, J.M. Falcipain inhibitors: optimization studies of the 2-pyrimidinecarbonitrile lead series. J. Med. Chem., 2010, 53(16), 6129-6152.
[http://dx.doi.org/10.1021/jm100556b] [PMID: 20672841 ]
[23]
Olson, J.E.; Lee, G.K.; Semenov, A.; Rosenthal, P.J. Antimalarial effects in mice of orally administered peptidyl cysteine protease inhibitors. Bioorg. Med. Chem., 1999, 7(4), 633-638.
[http://dx.doi.org/10.1016/S0968-0896(99)00004-8] [PMID: 10353642 ]
[24]
Lee, B.J.; Singh, A.; Chiang, P.; Kemp, S.J.; Goldman, E.A.; Weinhouse, M.I.; Vlasuk, G.P.; Rosenthal, P.J. Antimalarial activities of novel synthetic cysteine protease inhibitors. Agents Chemother., 2003, 47(12), 3810-3814.
[http://dx.doi.org/10.1128/AAC.47.12.3810-3814.2003]
[25]
Huang, H.; Lu, W.; Li, X.; Cong, X.; Ma, H.; Liu, X.; Zhang, Y.; Che, P.; Ma, R.; Li, H.; Shen, X.; Jiang, H.; Huang, J.; Zhu, J. Design and synthesis of small molecular dual inhibitor of falcipain-2 and dihydrofolate reductase as antimalarial agent. Bioorg. Med. Chem. Lett., 2012, 22(2), 958-962.
[http://dx.doi.org/10.1016/j.bmcl.2011.12.011] [PMID: 22192590 ]
[26]
Biot, C.; Pradines, B.; Sergeant, M.H.; Gut, J.; Rosenthal, P.J.; Chibale, K. Design, synthesis, and antimalarial activity of structural chimeras of thiosemicarbazone and ferroquine analogues. Bioorg. Med. Chem. Lett., 2007, 17(23), 6434-6438.
[http://dx.doi.org/10.1016/j.bmcl.2007.10.003] [PMID: 17949976 ]
[27]
Rosenthal, P.J. Plasmodium falciparum: effects of proteinase inhibitors on globin hydrolysis by cultured malaria parasites. Exp. Parasitol., 1995, 80(2), 272-281.
[http://dx.doi.org/10.1006/expr.1995.1033] [PMID: 7895837 ]
[28]
Semenov, A.; Olson, J.E.; Rosenthal, P.J. Antimalarial synergy of cysteine and aspartic protease inhibitors. Antimicrob. Agents Chemother., 1998, 42(9), 2254-2258.
[http://dx.doi.org/10.1128/AAC.42.9.2254] [PMID: 9736544 ]
[29]
Ettari, R.; Bova, F.; Zappalà, M.; Grasso, S.; Micale, N. Falcipain-2 inhibitors. Med. Res. Rev., 2010, 30(1), 136-167.
[http://dx.doi.org/10.1002/med.20163] [PMID: 19526594 ]
[30]
Li, H.; Aneja, R.; Chaiken, I. Click chemistry in peptide-based drug design. Molecules, 2013, 18(8), 9797-9817.
[http://dx.doi.org/10.3390/molecules18089797] [PMID: 23959192 ]
[31]
Shah, F.; Wu, Y.; Gut, J.; Pedduri, Y.; Legac, J.; Rosenthal, P.J.; Avery, M.A. Design, synthesis and biological evaluation of novel benzothiazole and triazole analogs as falcipain inhibitors. MedChemComm, 2011, 2(12), 1201-1207.
[http://dx.doi.org/10.1039/c1md00129a]
[32]
Hans, R.H.; Gut, J.; Rosenthal, P.J.; Chibale, K. Comparison of the antiplasmodial and falcipain-2 inhibitory activity of β-amino alcohol thiolactone-chalcone and isatin-chalcone hybrids. Bioorg. Med. Chem. Lett., 2010, 20(7), 2234-2237.
[http://dx.doi.org/10.1016/j.bmcl.2010.02.017] [PMID: 20206517 ]
[33]
Chu, X.M.; Wang, C.; Wang, W.L.; Liang, L.L.; Liu, W.; Gong, K.K.; Sun, K.L. Triazole derivatives and their antiplasmodial and antimalarial activities. Eur. J. Med. Chem., 2019, 166, 206-223.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.047] [PMID: 30711831]
[34]
Roy, K.K. Targeting the active sites of malarial proteases for antimalarial drug discovery: approaches, progress and challenges. Int. J. Antimicrob. Agents, 2017, 50(3), 287-302.
[http://dx.doi.org/10.1016/j.ijantimicag.2017.04.006] [PMID: 28668681 ]
[35]
Masood, M.M.; Hasan, P.; Tabrez, S.; Ahmad, M.B.; Yadava, U.; Daniliuc, C.G.; Sonawane, Y.A.; Azam, A.; Rub, A.; Abid, M. Anti-leishmanial and cytotoxic activities of amino acid-triazole hybrids: Synthesis, biological evaluation, molecular docking and in silico physico-chemical properties. Bioorg. Med. Chem. Lett., 2017, 27(9), 1886-1891.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.049] [PMID: 28359789 ]
[36]
Fan, Y.L.; Ke, X.; Li, M. Coumarin-triazole hybrids and their biological activities. J. Heterocycl. Chem., 2018, 1(55), 791-802.
[http://dx.doi.org/10.1002/jhet.312]
[37]
Dheer, D.; Singh, V.; Shankar, R. Medicinal attributes of 1,2,3-triazoles: Current developments. Bioorg. Chem., 2017, 71(71), 30-54.
[http://dx.doi.org/10.1016/j.bioorg.2017.01.010] [PMID: 28126288]
[38]
Zhang, S.; Xu, Z.; Gao, C.; Ren, Q.C.; Chang, L.; Lv, Z.S.; Feng, L.S. Triazole derivatives and their anti-tubercular activity. Eur. J. Med. Chem., 2017, 138(138), 501-513.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.051] [PMID: 28692915]
[39]
Kaur, K.; Jain, M.; Reddy, R.P.; Jain, R. Quinolines and structurally related heterocycles as antimalarials. Eur. J. Med. Chem., 2010, 45(8), 3245-3264.
[http://dx.doi.org/10.1016/j.ejmech.2010.04.011] [PMID: 20466465 ]
[40]
Hu, Y.Q.; Xu, Z.; Zhang, S.; Wu, X.; Ding, J.W.; Lv, Z.S.; Feng, L.S. Recent developments of coumarin-containing derivatives and their anti-tubercular activity. Eur. J. Med. Chem., 2017, 136, 122-130.
[http://dx.doi.org/10.1016/j.ejmech.2017.05.004] [PMID: 28494250 ]
[41]
Frederich, M.; Tits, M.; Angenot, L. Potential antimalarial activity of indole alkaloids. Trans. R. Soc. Trop. Med. Hyg., 2008, 102(1), 11-19.
[http://dx.doi.org/10.1016/j.trstmh.2007.10.002] [PMID: 18035385 ]
[42]
Nivsarkar, M.; Thavaselvam, D.; Prasanna, S.; Sharma, M.; Kaushik, M.P. Design, synthesis and biological evaluation of novel bicyclic β-lactams as potential antimalarials. Bioorg. Med. Chem. Lett., 2005, 15(5), 1371-1373.
[http://dx.doi.org/10.1016/j.bmcl.2005.01.011] [PMID: 15713389]
[43]
Chizema, M.; Mabasa, T.F.; Hoppe, H.C.; Kinfe, H.H. Design, synthesis, and antiplasmodial evaluation of a series of novel sulfoximine analogues of carbohydrate-based thiochromans. Chem. Biol. Drug Des., 2019, 93(3), 254-261.
[http://dx.doi.org/10.1111/cbdd.13408] [PMID: 30264436]
[44]
Patil, V.; Guerrant, W.; Chen, P.C.; Gryder, B.; Benicewicz, D.B.; Khan, S.I.; Tekwani, B.L.; Oyelere, A.K.; Oyelere, A.K. Antimalarial and antileishmanial activities of histone deacetylase inhibitors with triazole-linked cap group. Bioorg. Med. Chem., 2010, 18(1), 415-425.
[http://dx.doi.org/10.1016/j.bmc.2009.10.042] [PMID: 19914074 ]
[45]
Baldwin, J.; Farajallah, A.M.; Malmquist, N.A.; Rathod, P.K.; Phillips, M.A. Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specificity. J. Biol. Chem., 2002, 277(44), 41827-41834.
[http://dx.doi.org/10.1074/jbc.M206854200] [PMID: 12189151]
[46]
Tarawneh, A.H.; Al-Momani, L.A.A.; León, F.; Jain, S.K.; Gadetskaya, A.V.; Abu-Orabi, S.T.; Tekwani, B.L.; Cutler, S.J. Evaluation of triazole and isoxazole derivatives as potential antiinfective agents. Med. Chem. Res., 2018, 27(4), 1269-1275.
[http://dx.doi.org/10.1007/s00044-018-2146-4] [PMID: 30374214 ]
[47]
Aneja, B.; Irfan, M.; Kapil, C.; Jairajpuri, M.A.; Maguire, R.; Kavanagh, K.; Rizvi, M.M.; Manzoor, N.; Azam, A.; Abid, M. Effect of novel triazole-amino acid hybrids on growth and virulence of Candida species: in vitro and in vivo studies. Org. Biomol. Chem., 2016, 14(45), 10599-10619.
[http://dx.doi.org/10.1039/C6OB01718E] [PMID: 27735963 ]
[48]
Mohammad, T.; Khan, F.I.; Lobb, K.A.; Islam, A.; Ahmad, F.; Hassan, M.I. Identification and evaluation of bioactive natural products as potential inhibitors of human microtubule affinity-regulating kinase 4 (MARK4). J. Biomol. Struct. Dyn., 2018, 37(7), 1-17.
[http://dx.doi.org/10.1080/07391102.2018.1468282] [PMID: 29683402 ]
[49]
Reilly, H.B.; Wang, H.; Steuter, J.A.; Marx, A.M.; Ferdig, M.T. Quantitative dissection of clone-specific growth rates in cultured malaria parasites. Int. J. Parasitol., 2007, 37(14), 1599-1607.
[http://dx.doi.org/10.1016/j.ijpara.2007.05.003] [PMID: 17585919 ]
[50]
Makler, M.T.; Hinrichs, D.J. Measurement of the lactate dehydrogenase activity of Plasmodium falciparum as an assessment of parasitemia. Am. J. Trop. Med. Hyg., 1993, 48(2), 205-210.
[http://dx.doi.org/10.4269/ajtmh.1993.48.205] [PMID: 8447524]
[51]
Evans, B.C.; Nelson, C.E.; Yu, S.S.; Beavers, K.R.; Kim, A.J.; Li, H.; Nelson, H.M.; Giorgio, T.D.; Duvall, C.L. Ex vivo red blood cell hemolysis assay for the evaluation of pH-responsive endosomolytic agents for cytosolic delivery of biomacromolecular drugs. J. Vis. Exp., 2013, 73 e50166
[http://dx.doi.org/10.3791/50166] [PMID: 23524982 ]
[52]
Woerdenbag, H.J.; Moskal, T.A.; Pras, N.; Malingré, T.M.; el-Feraly, F.S.; Kampinga, H.H.; Konings, A.W. Cytotoxicity of artemisinin-related endoperoxides to Ehrlich ascites tumor cells. J. Nat. Prod., 1993, 56(6), 849-856.
[http://dx.doi.org/10.1021/np50096a007] [PMID: 8350087 ]
[53]
Moneriz, C.; Marín-García, P.; García-Granados, A.; Bautista, J.M.; Diez, A.; Puyet, A. Parasitostatic effect of maslinic acid. I. Growth arrest of Plasmodium falciparum intraerythrocytic stages. Malar. J., 2011, 10(1), 82.
[http://dx.doi.org/10.1186/1475-2875-10-82] [PMID: 21477369]
[54]
Sijwali, P.S.; Brinen, L.S.; Rosenthal, P.J. Systematic optimization of expression and refolding of the Plasmodium falciparum cysteine protease falcipain-2. Protein Expr. Purif., 2001, 22(1), 128-134.
[http://dx.doi.org/10.1006/prep.2001.1416] [PMID: 11388810 ]
[55]
Cruz, L.N.; Juliano, M.A.; Budu, A.; Juliano, L.; Holder, A.A.; Blackman, M.J.; Garcia, C.R. Extracellular ATP triggers proteolysis and cytosolic Ca2+ rise in Plasmodium berghei and Plasmodium yoelii malaria parasites. Malar. J., 2012, 11(1), 69.
[http://dx.doi.org/10.1186/1475-2875-11-69] [PMID: 22420332]
[56]
Moon, S.U.; Kang, J.M.; Kim, T.S.; Kong, Y.; Sohn, W.M.; Na, B.K. Plasmodium vivax: collaborative roles for plasmepsin 4 and vivapains in hemoglobin hydrolysis. Exp. Parasitol., 2011, 128(2), 127-132.
[http://dx.doi.org/10.1016/j.exppara.2011.02.015] [PMID: 21334328]
[57]
Men, T.T.; Huy, N.T.; Trang, D.T.; Shuaibu, M.N.; Hirayama, K.; Kamei, K. A simple and inexpensive haemozoin-based colorimetric method to evaluate anti-malarial drug activity. Malar. J., 2012, 11, 272.
[http://dx.doi.org/10.1186/1475-2875-11-272] [PMID: 22877238]
[58]
Boechat, N. Ferreira, Mde.L.; Pinheiro, L.C.; Jesus, A.M.; Leite, M.M.; Júnior, C.C.; Aguiar, A.C.; de Andrade, I.M.; Krettli, A.U. New compounds hybrids 1h-1,2,3-triazole-quinoline against Plasmodium falciparum. Chem. Biol. Drug Des., 2014, 84(3), 325-332.
[http://dx.doi.org/10.1111/cbdd.12321] [PMID: 24803084 ]
[59]
Rowe, J.A.; Claessens, A.; Corrigan, R.A.; Arman, M. Adhesion of Plasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications. Expert Rev. Mol. Med., 2009, 11 e16
[http://dx.doi.org/10.1017/S1462399409001082] [PMID: 19467172 ]
[60]
Dahl, E.L.; Rosenthal, P.J. Biosynthesis, localization, and processing of falcipain cysteine proteases of Plasmodium falciparum. Mol. Biochem. Parasitol., 2015, 139(2), 205-212.
[61]
Gupta, P.; Mehrotra, S.; Sharma, A.; Chugh, M.; Pandey, R.; Kaushik, A.; Khurana, S.; Srivastava, N.; Srivastava, T.; Deshmukh, A.; Panda, A.; Aggarwal, P.; Bhavesh, N.S.; Bhatnagar, R.K.; Mohmmed, A.; Gupta, D.; Malhotra, P. Exploring heme and hemoglobin binding regions of Plasmodium heme detoxification protein for new antimalarial discovery. J. Med. Chem., 2017, 60(20), 8298-8308.
[http://dx.doi.org/10.1021/acs.jmedchem.7b00089] [PMID: 28949547]
[62]
Farias, S.L.; Gazarini, M.L.; Melo, R.L.; Hirata, I.Y.; Juliano, M.A.; Juliano, L.; Garcia, C.R. Cysteine-protease activity elicited by Ca2+ stimulus in Plasmodium. Mol. Biochem. Parasitol., 2005, 141(1), 71-79.
[http://dx.doi.org/10.1016/j.molbiopara.2005.01.015] [PMID: 15811528]
[63]
Pandey, K.C.; Wang, S.X.; Sijwali, P.S.; Lau, A.L.; McKerrow, J.H.; Rosenthal, P.J. The Plasmodium falciparum cysteine protease falcipain-2 captures its substrate, hemoglobin, via a unique motif. Proc. Natl. Acad. Sci. USA, 2005, 102(26), 9138-9143.
[http://dx.doi.org/10.1073/pnas.0502368102] [PMID: 15964982 ]
[64]
Grazioso, G.; Legnani, L.; Toma, L.; Ettari, R.; Micale, N.; De Micheli, C. Mechanism of falcipain-2 inhibition by α,β-unsaturated benzo[1,4]diazepin-2-one methyl ester. J. Comput. Aided Mol. Des., 2012, 26(9), 1035-1043.
[http://dx.doi.org/10.1007/s10822-012-9596-4] [PMID: 22965332 ]
[65]
Lehmann, C.; Tan, M.S.Y.; de Vries, L.E.; Russo, I.; Sanchez, M.I.; Goldberg, D.E.; Deu, E. Plasmodium falciparum dipeptidyl aminopeptidase 3 activity is important for efficient erythrocyte invasion by the malaria parasite. PLoS Pathog., 2018, 14(5) e1007031
[http://dx.doi.org/10.1371/journal.ppat.1007031] [PMID: 29768491]
[66]
Huy, N.T.; Shima, Y.; Maeda, A.; Men, T.T.; Hirayama, K.; Hirase, A.; Miyazawa, A.; Kamei, K. Phospholipid membrane-mediated hemozoin formation: the effects of physical properties and evidence of membrane surrounding hemozoin. PLoS One, 2013, 8(7) e70025
[http://dx.doi.org/10.1371/journal.pone.0070025] [PMID: 23894579 ]
[67]
Gorka, A.P.; Alumasa, J.N.; Sherlach, K.S.; Jacobs, L.M.; Nickley, K.B.; Brower, J.P.; de Dios, A.C.; Roepe, P.D. Cytostatic versus cytocidal activities of chloroquine analogues and inhibition of hemozoin crystal growth. Antimicrob. Agents Chemother., 2013, 57(1), 356-364.
[http://dx.doi.org/10.1128/AAC.01709-12] [PMID: 23114783 ]
[68]
Huy, N.T.; Kamei, K.; Yamamoto, T.; Kondo, Y.; Kanaori, K.; Takano, R.; Tajima, K.; Hara, S. Clotrimazole binds to heme and enhances heme-dependent hemolysis: proposed antimalarial mechanism of clotrimazole. J. Biol. Chem., 2002, 277(6), 4152-4158.
[http://dx.doi.org/10.1074/jbc.M107285200] [PMID: 11707446 ]
[69]
Francis, S.E.; Sullivan, D.J., Jr; Goldberg, D.E. Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu. Rev. Microbiol., 1997, 51, 97-123.
[http://dx.doi.org/10.1146/annurev.micro.51.1.97] [PMID: 9343345 ]
[70]
Tekwani, B.L.; Walker, L.A. Targeting the hemozoin synthesis pathway for new antimalarial drug discovery: technologies for in vitro beta-hematin formation assay. Comb. Chem. High Throughput Screen., 2005, 8(1), 63-79.
[http://dx.doi.org/10.2174/1386207053328101] [PMID: 15720198 ]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 20
ISSUE: 5
Year: 2020
Page: [377 - 389]
Pages: 13
DOI: 10.2174/1568026620666200130162347
Price: $65

Article Metrics

PDF: 20
HTML: 2