Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
General Research Article

Tweaking α -Galactoceramides: Probing the Dynamical Mechanisms of Improved Recognition for Invariant Natural Killer T-cell Receptor in Cancer Immunotherapeutics

Author(s): Houda Washah, Clement Agoni, Fisayo A. Olotu, Geraldene Munsamy and Mahmoud E.S. Soliman*

Volume 21, Issue 13, 2020

Page: [1354 - 1367] Pages: 14

DOI: 10.2174/1389201020666191118103342

Price: $65

Abstract

Background: The last few decades have witnessed groundbreaking research geared towards immune surveillance mechanisms and have yielded significant improvements in the field of cancer immunotherapy. This approach narrows down on the development of therapeutic agents that either activate or enhance the recognitive function of the immune system to facilitate the destruction of malignant cells. The α -galactosylceramide derivative, KRN7000, is an immunotherapeutic agent that has gained attention due to its pharmacological ability to activate CD1d-restricted invariant natural killer T(iNKT) cells with notable potency against cancer cells in mouse models; a therapeutic success was not well replicated in human models. Dual structural modification of KRN7000 entailing the incorporation of hydrocinnamoyl ester on C6" and C4-OH truncation of the sphingoid base led to the development of AH10-7 which, interestingly, exhibited high potency in human cells.

Objective/Methods: Therefore, to gain molecular insights into the structural dynamics and selective mechanisms of AH10-7 for human variants, we employed integrative molecular dynamics simulations and thermodynamic calculations to investigate the inhibitory activities of KRN7000 andAH10-7 on hTCR-CD1d towards activating iNKT.

Results: Interestingly, our findings revealed that AH10-7 exhibited higher affinity binding and structural effects on hTCR-CD1d, as mediated by the incorporated hydrocinnamoyl ester moiety which accounted for stronger intermolecular interactions with ‘non-common’ binding site residues.

Conclusion: Findings extracted from this study further reveal important molecular and structural perspectives that could aid in the design of novel α-GalCer derivatives for cancer immunotherapeutics.

Keywords: Cancer immunotherapy, natural killer T-cells, dual modification, immunotherapeutics, AH10-7 α-galactosylceramide.

« Previous Next »
Graphical Abstract

[1]
Ribatti, D. The concept of immune surveillance against tumors. The first theories. Oncotarget, 2017, 8(4), 7175-7180.
[http://dx.doi.org/10.18632/oncotarget.12739] [PMID: 27764780]
[2]
Dellabona, P.; Padovan, E.; Casorati, G.; Brockhaus, M.; Lanzavecchia, A. An invariant V α 24-J α Q/V β 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells. J. Exp. Med., 1994, 180(3), 1171-1176.
[http://dx.doi.org/10.1084/jem.180.3.1171] [PMID: 8064234]
[3]
Lantz, O.; Bendelac, A. An invariant T cell receptor α chain is used by a unique subset of major histocompatibility complex class I-specific CD4+ and CD4-8- T cells in mice and humans. J. Exp. Med., 1994, 180(3), 1097-1106.
[http://dx.doi.org/10.1084/jem.180.3.1097] [PMID: 7520467]
[4]
McEwen-Smith, R.M.; Salio, M.; Cerundolo, V. The regulatory role of invariant NKT cells in tumor immunity. Cancer Immunol. Res., 2015, 3(5), 425-435.
[http://dx.doi.org/10.1158/2326-6066.CIR-15-0062] [PMID: 25941354]
[5]
Lam, P.Y.; Nissen, M.D.; Mattarollo, S.R. Invariant natural killer T cells in immune regulation of blood cancers: Harnessing their potential in immunotherapies. Front. Immunol., 2017, 8, 1355.
[http://dx.doi.org/10.3389/fimmu.2017.01355] [PMID: 29109728]
[6]
Brennan, P.J.; Brigl, M.; Brenner, M.B. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat. Rev. Immunol., 2013, 13(2), 101-117.
[http://dx.doi.org/10.1038/nri3369] [PMID: 23334244]
[7]
Bendelac, A.; Savage, P.B.; Teyton, L. The biology of NKT cells. Annu. Rev. Immunol., 2007, 25, 297-336.
[http://dx.doi.org/10.1146/annurev.immunol.25.022106.141711] [PMID: 17150027]
[8]
Macho-Fernandez, E.; Brigl, M. The extended family of CD1d-restricted NKT Cells: sifting through a mixed bag of TCRs, antigens, and functions. Front. Immunol., 2015, 6, 362.
[http://dx.doi.org/10.3389/fimmu.2015.00362] [PMID: 26284062]
[9]
Crosby, C.M.; Kronenberg, M. Tissue-specific functions of invariant natural killer T cells. Nat. Rev. Immunol., 2018, 18(9), 559-574.
[http://dx.doi.org/10.1038/s41577-018-0034-2 ] [PMID: 29967365]
[10]
Rossjohn, J.; Pellicci, D.G.; Patel, O.; Gapin, L.; Godfrey, D.I. Recognition of CD1d-restricted antigens by natural killer T cells. Nat. Rev. Immunol., 2012, 12(12), 845-857.
[http://dx.doi.org/10.1038/nri3328] [PMID: 23154222]
[11]
Burdin, N.; Brossay, L.; Koezuka, Y.; Smiley, S.T.; Grusby, M.J.; Gui, M.; Taniguchi, M.; Hayakawa, K.; Kronenberg, M. Selective ability of mouse CD1 to present glycolipids: α-galactosylceramide specifically stimulates V α 14+ NK T lymphocytes. J. Immunol., 1998, 161(7), 3271-3281.
[PMID: 9759842]
[12]
Jones, E.Y.; Salio, M.; Cerundolo, V. T cell receptors get back to basics. Nat. Immunol., 2007, 8(10), 1033-1035.
[http://dx.doi.org/10.1038/ni1007-1033] [PMID: 17878911]
[13]
Dougan, S.K.; Kaser, A.; Blumberg, R.S. CD1 expression on antigen-presenting cells. Curr. Top. Microbiol. Immunol., 2007, 314, 113-141.
[http://dx.doi.org/10.1007/978-3-540-69511-0_5]
[14]
Griewank, K.; Borowski, C.; Rietdijk, S.; Wang, N.; Julien, A.; Wei, D.G.; Mamchak, A.A.; Terhorst, C.; Bendelac, A. Homotypic interactions mediated by Slamf1 and Slamf6 receptors control NKT cell lineage development. Immunity, 2007, 27(5), 751-762.
[http://dx.doi.org/10.1016/j.immuni.2007.08.020] [PMID: 18031695]
[15]
Coquet, J.M.; Chakravarti, S.; Kyparissoudis, K.; McNab, F.W.; Pitt, L.A.; McKenzie, B.S.; Berzins, S.P.; Smyth, M.J.; Godfrey, D.I. Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population. Proc. Natl. Acad. Sci. USA, 2008, 105(32), 11287-11292.
[http://dx.doi.org/10.1073/pnas.0801631105] [PMID: 18685112]
[16]
Lynch, L.; Michelet, X.; Zhang, S.; Brennan, P.J.; Moseman, A.; Lester, C.; Besra, G.; Vomhof-Dekrey, E.E.; Tighe, M.; Koay, H.F.; Godfrey, D.I.; Leadbetter, E.A.; Sant’Angelo, D.B.; von Andrian, U.; Brenner, M.B. Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat. Immunol., 2015, 16(1), 85-95.
[http://dx.doi.org/10.1038/ni.3047] [PMID: 25436972]
[17]
Lynch, L.; Nowak, M.; Varghese, B.; Clark, J.; Hogan, A.E.; Toxavidis, V.; Balk, S.P.; O’Shea, D.; O’Farrelly, C.; Exley, M.A. Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity, 2012, 37(3), 574-587.
[http://dx.doi.org/10.1016/j.immuni.2012.06.016] [PMID: 22981538]
[18]
Stetson, D.B.; Mohrs, M.; Reinhardt, R.L.; Baron, J.L.; Wang, Z.E.; Gapin, L.; Kronenberg, M.; Locksley, R.M. Constitutive cytokine mRNAs mark Natural Killer (NK) and NK T cells poised for rapid effector function. J. Exp. Med., 2003, 198(7), 1069-1076.
[http://dx.doi.org/10.1084/jem.20030630] [PMID: 14530376]
[19]
Beyaz, S.; Kim, J.H.; Pinello, L.; Xifaras, M.E.; Hu, Y.; Huang, J.; Kerenyi, M.A.; Das, P.P.; Barnitz, R.A.; Herault, A.; Dogum, R.; Haining, W.N.; Yilmaz, Ö.H.; Passegue, E.; Yuan, G.C.; Orkin, S.H.; Winau, F. The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells. Nat. Immunol., 2017, 18(2), 184-195.
[http://dx.doi.org/10.1038/ni.3644] [PMID: 27992400]
[20]
Wesley, J.D.; Tessmer, M.S.; Chaukos, D.; Brossay, L. NK cell-like behavior of Valpha14i NK T cells during MCMV infection. PLoS Pathog., 2008, 4(7)e1000106
[http://dx.doi.org/10.1371/journal.ppat.1000106] [PMID: 18636102]
[21]
Nieuwenhuis, E.E.S.; Matsumoto, T.; Exley, M.; Schleipman, R.A.; Glickman, J.; Bailey, D.T.; Corazza, N.; Colgan, S.P.; Onderdonk, A.B.; Blumberg, R.S. CD1d-dependent macrophage-mediated clearance of Pseudomonas aeruginosa from lung. Nat. Med., 2002, 8(6), 588-593.
[http://dx.doi.org/10.1038/nm0602-588] [PMID: 12042809]
[22]
Schmieg, J.; Yang, G.; Franck, R.W.; Van Rooijen, N.; Tsuji, M. Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion. Proc. Natl. Acad. Sci. USA, 2005, 102(4), 1127-1132.
[http://dx.doi.org/10.1073/pnas.0408288102] [PMID: 15644449]
[23]
Monteiro, M.; Graca, L. iNKT cells: Innate lymphocytes with a diverse response. Crit. Rev. Immunol., 2014, 34(1), 81-90.
[http://dx.doi.org/10.1615/CritRevImmunol.2014010088] [PMID: 24579702]
[24]
Yamashita, K.; Arimoto, A.; Nishi, M.; Tanaka, T.; Fujita, M.; Fukuoka, E.; Sugita, Y.; Nakagawa, A.; Hasegawa, H.; Suzuki, S.; Kakeji, Y. Application of iNKT cell-targeted active immunotherapy in cancer treatment. Anticancer Res., 2018, 38(7), 4233-4239.
[http://dx.doi.org/10.21873/anticanres.12719] [PMID: 29970556]
[25]
Crowe, N.Y.; Smyth, M.J.; Godfrey, D.I. A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J. Exp. Med., 2002, 196(1), 119-127.
[http://dx.doi.org/10.1084/jem.20020092] [PMID: 12093876]
[26]
Cerundolo, V.; Salio, M. Harnessing NKT cells for therapeutic applications. Curr. Top. Microbiol. Immunol., 2007, 314, 325-340.
[http://dx.doi.org/10.1007/978-3-540-69511-0_13] [PMID: 17593667]
[27]
Bedard, M.; Salio, M.; Cerundolo, V. Harnessing the power of invariant natural killer T cells in cancer immunotherapy. Front. Immunol., 2017, 8, 1829.
[http://dx.doi.org/10.3389/fimmu.2017.01829] [PMID: 29326711]
[28]
Morita, M.; Motoki, K.; Akimoto, K.; Natori, T.; Sakai, T.; Sawa, E.; Yamaji, K.; Koezuka, Y.; Kobayashi, E.; Fukushima, H. Structure-activity relationship of alpha-galactosylceramides against B16-bearing mice. J. Med. Chem., 1995, 38(12), 2176-2187.
[http://dx.doi.org/10.1021/jm00012a018] [PMID: 7783149]
[29]
Kawano, T.; Cui, J.; Koezuka, Y.; Toura, I.; Kaneko, Y.; Motoki, K.; Ueno, H.; Nakagawa, R.; Sato, H.; Kondo, E.; Koseki, H.; Taniguchi, M. CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science, 1997, 278(5343), 1626-1629.
[http://dx.doi.org/10.1126/science.278.5343.1626] [PMID: 9374463]
[30]
Natori, T.; Morita, M.; Akimoto, K.; Koezuka, Y. Agelasphins, novel antitumor and immunostimulatory cerebrosides from the marine sponge Agelas-mauritianus. Tetrahedron, 1994, 50, 2771-2784.
[http://dx.doi.org/10.1016/S0040-4020(01)86991-X]
[31]
Kharkwal, S.S.; Arora, P.; Porcelli, S.A. Glycolipid activators of invariant NKT cells as vaccine adjuvants. Immunogenetics, 2016, 68(8), 597-610.
[http://dx.doi.org/10.1007/s00251-016-0925-y] [PMID: 27377623]
[32]
Kobayashi, E.; Motoki, K.; Uchida, T.; Fukushima, H.; Koezuka, Y. KRN7000, a novel immunomodulator, and its antitumor activities. Oncol. Res., 1995, 7(10-11), 529-534.
[PMID: 8866665]
[33]
Kronenberg, M.; Gapin, L. The unconventional lifestyle of NKT cells. Nat. Rev. Immunol., 2002, 2(8), 557-568.
[http://dx.doi.org/10.1038/nri854] [PMID: 12154375]
[34]
Chennamadhavuni, D.; Saavedra-Avila, N.A.; Carreño, L.J.; Guberman-Pfeffer, M.J.; Arora, P.; Yongqing, T.; Pryce, R.; Koay, H.F.; Godfrey, D.I.; Keshipeddy, S.; Richardson, S.K.; Sundararaj, S.; Lo, J.H.; Wen, X.; Gascón, J.A.; Yuan, W.; Rossjohn, J.; Le Nours, J.; Porcelli, S.A.; Howell, A.R. Dual modifications of α-galactosylceramide synergize to promote activation of human invariant natural killer T cells and stimulate anti-tumor immunity. Cell Chem. Biol., 2018, 25(5), 571-584.e8.
[http://dx.doi.org/10.1016/j.chembiol.2018.02.009] [PMID: 29576533]
[35]
Nair, S.; Dhodapkar, M.V. Natural killer T cells in cancer immunotherapy. Front. Immunol., 2017, 8, 1178.
[http://dx.doi.org/10.3389/fimmu.2017.01178] [PMID: 29018445]
[36]
Yu, K.O.; Porcelli, S.A. The diverse functions of CD1d-restricted NKT cells and their potential for immunotherapy. Immunol. Lett., 2005, 100(1), 42-55.
[http://dx.doi.org/10.1016/j.imlet.2005.06.010] [PMID: 16083968]
[37]
Laurent, X.; Bertin, B.; Renault, N.; Farce, A.; Speca, S.; Milhomme, O.; Millet, R.; Desreumaux, P.; Hénon, E.; Chavatte, P. Switching invariant natural killer T (iNKT) cell response from anticancerous to anti-inflammatory effect: molecular bases. J. Med. Chem., 2014, 57(13), 5489-5508.
[http://dx.doi.org/10.1021/jm4010863] [PMID: 24428717]
[38]
Kopecky-Bromberg, S.A.; Fraser, K.A.; Pica, N.; Carnero, E.; Moran, T.M.; Franck, R.W.; Tsuji, M.; Palese, P. Alpha-C-galactosylceramide as an adjuvant for a live attenuated influenza virus vaccine. Vaccine, 2009, 27(28), 3766-3774.
[http://dx.doi.org/10.1016/j.vaccine.2009.03.090] [PMID: 19464560]
[39]
Salmaso, V.; Moro, S. Bridging molecular docking to molecular dynamics in exploring ligand-protein recognition process: An overview. Front. Pharmacol., 2018, 9, 923.
[http://dx.doi.org/10.3389/fphar.2018.00923] [PMID: 30186166]
[40]
Salmaso, V. Exploring protein flexibility during docking to investigate ligand-target recognition (Ph.D. Thesis),, 2018.http://paduaresearch.cab.unipd.it/10780/
[41]
Berman, H.M.; Battistuz, T.; Bhat, T.N.; Bluhm, W.F. The protein data bank. Acta Crystallogr. D Biol. Crystallogr.,, 2002, 58(Pt 6 No 1), 899-907.
[42]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--a visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612.
[http://dx.doi.org/10.1002/jcc.20084] [PMID: 15264254]
[43]
Case, D.; Cheatham, T.E.I.; Darden, T.; Gohlke, H.; Luo, R.K.M.; Merz, J.; Onufriev, A.; Simmerling, C.; Wang, B.; Woods, R. The amber biomelecular simulation programs. J. Comput. Chem., 2005, 26, 1668-1688.
[http://dx.doi.org/10.1002/jcc.20290] [PMID: 16200636]
[44]
Grest, G.S.; Kremer, K. Molecular dynamics simulation for polymers in the presence of a heat bath. Phys. Rev. A Gen. Phys., 1986, 33(5), 3628-3631.
[http://dx.doi.org/10.1103/PhysRevA.33.3628] [PMID: 9897103]
[45]
Berendsen, H.J.C.; Postma, J.P.M.; van Gunsteren, W.F.; DiNola, A.; Haak, J.R. Molecular dynamics with coupling to an external bath. J. Chem. Phys., 1984, 81, 3684-3690.
[http://dx.doi.org/10.1063/1.448118]
[46]
Ryckaert, J.P.; Ciccotti, G.; Berendsen, H.J.C. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys., 1977, 23, 327-341.
[http://dx.doi.org/10.1016/0021-9991(77)90098-5]
[47]
Roe, D.R.; Cheatham, T.E. III PTRAJ and CPPTRAJ: Software for processing and analysis of molecular dynamics trajectory data. J. Chem. Theory Comput., 2013, 9(7), 3084-3095.
[http://dx.doi.org/10.1021/ct400341p] [PMID: 26583988]
[48]
Seifert, E. OriginPro 9.1: Scientific data analysis and graphing software-software review. J. Chem. Inf. Model., 2014, 54(5), 1552.
[http://dx.doi.org/10.1021/ci500161d] [PMID: 24702057]
[49]
Hou, T.; Wang, J.; Li, Y.; Wang, W.; Houa, T.; Wangb, J.; Lia, Y.; Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J. Chem. Inf. Model., 2011, 51(1), 69-82.
[http://dx.doi.org/10.1021/ci100275a] [PMID: 21117705]
[50]
Agoni, C.; Ramharack, P.; Soliman, M.E.S. Synergistic interplay of the co-administration of rifampin and newly developed anti-TB drug: Could it be a promising new line of TB therapy? Comb. Chem. High Throughput Screen., 2018, 21(6), 453-460.
[http://dx.doi.org/10.2174/1386207321666180716093617] [PMID: 30009705]
[51]
Agoni, C.; Ramharack, P.; Soliman, M.E.S. Allosteric inhibition induces an open WPD-loop: A new avenue towards glioblastoma therapy. RSC Advances, 2018, 8, 40187-40197.
[http://dx.doi.org/10.1039/C8RA08427K]
[52]
Agoni, C.; Ramharack, P.; Soliman, M.E. Co-inhibition as a strategic therapeutic approach to overcome rifampin resistance in tuberculosis therapy: Atomistic insights. Future Med. Chem., 2018, 10(14), 1665-1675.
[http://dx.doi.org/10.4155/fmc-2017-0197] [PMID: 29957065]
[53]
Munsamy, G.; Agoni, C.; Soliman, M.E.S. A dual target of Plasmepsin IX and X: Unveiling the atomistic superiority of a core chemical scaffold in malaria therapy. J. Cell. Biochem., 2018, •••, 1-12.
[PMID: 30430636]
[54]
Olotu, F.A.; Agoni, C.; Adeniji, E.; Abdullahi, M.; Soliman, M.E. Probing gallate-mediated selectivity and high-affinity binding of epigallocatechin gallate: A way-forward in the design of selective inhibitors for anti-apoptotic Bcl-2 proteins. Appl. Biochem. Biotechnol., 2019, 187(3), 1061-1080.
[http://dx.doi.org/10.1007/s12010-018-2863-7] [PMID: 30155742]
[55]
Miller, B.R., III; McGee, T.D., Jr; Swails, J.M.; Homeyer, N.; Gohlke, H.; Roitberg, A.E. MMPBSA.py: An efficient program for end-state free energy calculations. J. Chem. Theory Comput., 2012, 8(9), 3314-3321.
[http://dx.doi.org/10.1021/ct300418h] [PMID: 26605738]
[56]
Badichi Akher, F.; Farrokhzadeh, A.; Olotu, F.A.; Agoni, C.; Soliman, M.E.S. The irony of chirality - unveiling the distinct mechanistic binding and activities of 1-(3-(4-amino-5-(7-methoxy-5-methylbenzo[b]thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyrrolidin-1-yl)prop-2-en-1-one enantiomers as irreversible covalent FGFR4 inhibitors. Org. Biomol. Chem., 2019, 17(5), 1176-1190.
[http://dx.doi.org/10.1039/C8OB02811G] [PMID: 30644960]
[57]
Wu, G. Amino acids: Metabolism, functions, and nutrition. Amino Acids, 2009, 37(1), 1-17.
[http://dx.doi.org/10.1007/s00726-009-0269-0] [PMID: 19301095]
[58]
Mukherjee, J.; Gupta, M.N. Increasing importance of protein flexibility in designing biocatalytic processes. Biotechnol. Rep. (Amst.), 2015, 6, 119-123.
[http://dx.doi.org/10.1016/j.btre.2015.04.001] [PMID: 28626705]
[59]
Olotu, F.A.; Soliman, M.E.S. From mutational inactivation to aberrant gain-of-function: Unraveling the structural basis of mutant p53 oncogenic transition. J. Cell. Biochem., 2018, 119(3), 2646-2652.
[http://dx.doi.org/10.1002/jcb.26430] [PMID: 29058783]
[60]
Maiorov, V.N.; Crippen, G.M. Significance of root-mean-square deviation in comparing three-dimensional structures of globular proteins. J. Mol. Biol., 1994, 235(2), 625-634.
[http://dx.doi.org/10.1006/jmbi.1994.1017] [PMID: 8289285]
[61]
Knapp, B.; Frantal, S.; Cibena, M.; Schreiner, W.; Bauer, P. Is an intuitive convergence definition of molecular dynamics simulations solely based on the root mean square deviation possible? J. Comput. Biol., 2011, 18(8), 997-1005.
[http://dx.doi.org/10.1089/cmb.2010.0237] [PMID: 21702691]
[62]
Pitera, J.W. Expected distributions of root-mean-square positional deviations in proteins. J. Phys. Chem. B, 2014, 118(24), 6526-6530.
[http://dx.doi.org/10.1021/jp412776d] [PMID: 24655018]
[63]
Mhlongo, N.N.; Soliman, M.E.S. Single H5N1 influenza a neuraminidase mutation develops resistance to oseltamivir due to distorted conformational and drug binding landscape: Multiple molecular dynamics analyses. RSC Advances, 2015, 5, 10849-10861.
[http://dx.doi.org/10.1039/C4RA13494J]

Rights & Permissions Print Cite
Article Metrics
9
© 2024 Bentham Science Publishers | Privacy Policy