Emerging Marine Immunomodulatory Small-molecules (2010- Present)

Author(s): Ran Li, Yu-Cheng Gu, Wen Zhang*.

Journal Name: Current Chemical Biology

Volume 13 , Issue 3 , 2019

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Background: Immunomodulation-based therapy has achieved a breakthrough in the last decade, which stimulates the passion of searching for potential immunomodulatory substances in recent years.

Objective: Marine natural products are a unique source of immunomodulatory substances. This paper summarized the emerging marine natural small-molecules and related synthesized derivatives with immunomodulatory activities to provide readers an overview of these bioactive molecules and their potential in immunomodulation therapy.

Conclusion: An increasing number of immunomodulatory marine small-molecules with diverse intriguing structure-skeletons were discovered. They may serve as a basis for further studies of marine natural products for their chemistry, related mechanism of action and structure- activity relationships.

Keywords: Marine small-molecules, immunomodulator, immunostimulant, immunosuppressant, α- GalCer, Polyketides.

Kominsky DJ, Campbell EL, Colgan SP. Metabolic shifts in immunity and inflammation. J Immunol 2010; 184(8): 4062-8.
[http://dx.doi.org/10.4049/jimmunol.0903002] [PMID: 20368286]
Nakamura K, Smyth MJ. Targeting cancer-related inflammation in the era of immunotherapy. Immunol Cell Biol 2017; 95(4): 325-32.
[http://dx.doi.org/10.1038/icb.2016.126] [PMID: 27999432]
Benson RA, Brewer JM, Platt AM. Mechanisms of autoimmunity in human diseases: A critical review of current dogma. Curr Opin Rheumatol 2014; 26(2): 197-203.
[http://dx.doi.org/10.1097/BOR.0000000000000037] [PMID: 24445477]
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science 2011; 331(6024): 1565-70.
[http://dx.doi.org/10.1126/science.1203486] [PMID: 21436444]
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012; 12(4): 252-64.
[http://dx.doi.org/10.1038/nrc3239] [PMID: 22437870]
Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018; 359(6382): 1350-5.
[http://dx.doi.org/10.1126/science.aar4060] [PMID: 29567705]
Riley RS, June CH, Langer R, Mitchell MJ. Delivery technologies for cancer immunotherapy. Nat Rev Drug Discov 2019; 18(3): 175-96.
[http://dx.doi.org/10.1038/s41573-018-0006-z] [PMID: 30622344]
Wang M, Liu Y, Cheng Y, Wei Y, Wei X. Immune checkpoint blockade and its combination therapy with small-molecule inhibitors for cancer treatment. Biochim Biophys Acta Rev Cancer 2019; 1871(2): 199-224.
[http://dx.doi.org/10.1016/j.bbcan.2018.12.002] [PMID: 30605718]
Hamilou Z, Lavaud P, Loriot Y. Atezolizumab in urothelial bladder carcinoma. Future Oncol 2018; 14(4): 331-41.
[http://dx.doi.org/10.2217/fon-2017-0433] [PMID: 29135284]
Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med 2015; 372(4): 311-9.
[http://dx.doi.org/10.1056/NEJMoa1411087] [PMID: 25482239]
Sunshine J, Taube JM. PD-1/PD-L1 inhibitors. Curr Opin Pharmacol 2015; 23: 32-8.
[http://dx.doi.org/10.1016/j.coph.2015.05.011] [PMID: 26047524]
Catanzaro M, Corsini E, Rosini M, Racchi M, Lanni C. Immunomodulators inspired by nature: A review on curcumin and echinacea. Molecules 2018; 23(11): 2778.
[http://dx.doi.org/10.3390/molecules23112778] [PMID: 30373170]
Wang T, Wu X, Guo C, et al. Development of inhibitors of the programmed cell death-1/programmed cell death-ligand 1 signaling pathway. J Med Chem 2019; 62(4): 1715-30.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00990] [PMID: 30247903]
Han Y, Gao Y, He T, et al. PD-1/PD-L1 inhibitor screening of caffeoylquinic acid compounds using surface plasmon resonance spectroscopy. Anal Biochem 2018; 547: 52-6.
[http://dx.doi.org/10.1016/j.ab.2018.02.003] [PMID: 29428377]
Malve H. Exploring the ocean for new drug developments: Marine pharmacology. J Pharm Bioallied Sci 2016; 8(2): 83-91.
[http://dx.doi.org/10.4103/0975-7406.171700] [PMID: 27134458]
Wang X, Yu H, Xing R, Li P. Characterization, preparation, and purification of marine bioactive peptides. BioMed Res Int 2017.20179746720
[http://dx.doi.org/10.1155/2017/9746720] [PMID: 28761878]
Arya V, Gupta VK. A review on marine immunomodulators. Int J Pharm Life Sci 2011; 2(5): 751-8.
Zhang Y, Zhang R. Recent advances in analytical methods for the therapeutic drug monitoring of immunosuppressive drugs. Drug Test Anal 2018; 10(1): 81-94.
[http://dx.doi.org/10.1002/dta.2290] [PMID: 28851030]
Ferguson JF, Roberts-Lee K, Borcea C, Smith HM, Midgette Y, Shah R. Omega-3 polyunsaturated fatty acids attenuate inflammatory activation and alter differentiation in human adipocytes. J Nutr Biochem 2019; 64: 45-9.
[http://dx.doi.org/10.1016/j.jnutbio.2018.09.027] [PMID: 30428424]
Irie K, Yanagita RC, Nakagawa Y. Challenges to the development of bryostatin-type anticancer drugs based on the activation mechanism of protein kinase Cδ. Med Res Rev 2012; 32(3): 518-35.
[http://dx.doi.org/10.1002/med.20220] [PMID: 22539107]
Safaeinejad F, Bahrami S, Redl H, Niknejad H. Inhibition of inflammation, suppression of matrix metalloproteinases, induction of neurogenesis, and antioxidant property make bryostatin-1 a therapeutic choice for multiple sclerosis. Front Pharmacol 2018; 9: 625.
[http://dx.doi.org/10.3389/fphar.2018.00625] [PMID: 29971003]
Zhang LH, Longley RE, Koehn FE. Antiproliferative and immunosuppressive properties of microcolin A, a marine-derived lipopeptide. Life Sci 1997; 60(10): 751-62.
[http://dx.doi.org/10.1016/S0024-3205(96)00645-5] [PMID: 9064480]
Oh DC, Strangman WK, Kauffman CA, Jensen PR, Fenical W. Thalassospiramides A and B, immunosuppressive peptides from the marine bacterium Thalassospira sp. Org Lett 2007; 9(8): 1525-8.
[http://dx.doi.org/10.1021/ol070294u] [PMID: 17373804]
Bourguet-Kondracki ML, Martin MT, Guyot M. A new β-carboline alkaloid isolated from the marine sponge Hyrtios erecta. Tetrahedron Lett 1996; 37(20): 3457-60.
Romo D, Choi NS, Li S, Buchler I, Shi Z, Liu JO. Evidence for separate binding and scaffolding domains in the immunosuppressive and antitumor marine natural product, pateamine a: design, synthesis, and activity studies leading to a potent simplified derivative. J Am Chem Soc 2004; 126(34): 10582-8.
[http://dx.doi.org/10.1021/ja040065s] [PMID: 15327314]
Natori T, Koezuka Y, Higa T. Agelasphins, novel α-galactosylceramides from the marine sponge Agelas mauritianus. Tetrahedron Lett 1993; 34(35): 5591-2.
Giaccone G, Punt CJ, Ando Y, et al. A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res 2002; 8(12): 3702-9.
[PMID: 12473579]
Anderson BL, Teyton L, Bendelac A, Savage PB. Stimulation of natural killer T cells by glycolipids. Molecules 2013; 18(12): 15662-88.
[http://dx.doi.org/10.3390/molecules181215662] [PMID: 24352021]
Chang YJ, Huang JR, Tsai YC, et al. Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids. Proc Natl Acad Sci USA 2007; 104(25): 10299-304.
[http://dx.doi.org/10.1073/pnas.0703824104] [PMID: 17566107]
Gonzalez-Aseguinolaza G, Van Kaer L, Bergmann CC, et al. Natural killer T cell ligand α-galactosylceramide enhances protective immunity induced by malaria vaccines. J Exp Med 2002; 195(5): 617-24.
[http://dx.doi.org/10.1084/jem.20011889] [PMID: 11877484]
Huang Y, Chen A, Li X, et al. Enhancement of HIV DNA vaccine immunogenicity by the NKT cell ligand, alpha-galactosylceramide. Vaccine 2008; 26(15): 1807-16.
[http://dx.doi.org/10.1016/j.vaccine.2008.02.002] [PMID: 18329757]
Sada-Ovalle I, Sköld M, Tian T, Besra GS, Behar SM. α-galactosylceramide as a therapeutic agent for pulmonary Mycobacterium tuberculosis infection. Am J Respir Crit Care Med 2010; 182(6): 841-7.
[http://dx.doi.org/10.1164/rccm.200912-1921OC] [PMID: 20508216]
Uldrich AP, Crowe NY, Kyparissoudis K, et al. NKT cell stimulation with glycolipid antigen in vivo: Costimulation-dependent expansion, Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge. J Immunol 2005; 175(5): 3092-101.
[http://dx.doi.org/10.4049/jimmunol.175.5.3092] [PMID: 16116198]
Parekh VV, Wilson MT, Olivares-Villagómez D, et al. Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest 2005; 115(9): 2572-83.
[http://dx.doi.org/10.1172/JCI24762] [PMID: 16138194]
Harrak Y, Barra CM, Delgado A, Castaño AR, Llebaria A. Galacto-configured aminocyclitol phytoceramides are potent in vivo invariant natural killer T cell stimulators. J Am Chem Soc 2011; 133(31): 12079-84.
[http://dx.doi.org/10.1021/ja202610x] [PMID: 21728320]
Bi J, Wang J, Zhou K, Wang Y, Fang M, Du Y. Synthesis and biological activities of 5-Thio-α-GalCers. ACS Med Chem Lett 2015; 6(4): 476-80.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00046] [PMID: 25941558]
Wojno J, Jukes JP, Ghadbane H, et al. Amide analogues of CD1d agonists modulate iNKT-cell-mediated cytokine production. ACS Chem Biol 2012; 7(5): 847-55.
[http://dx.doi.org/10.1021/cb2005017] [PMID: 22324848]
Verma YK, Reddy BS, Pawar MS, Bhunia D, Sampath Kumar HM. Synthesis and immunological evaluation of benzyloxyalkyl-substituted 1,2,3-triazolyl α-GalCer analogues. ACS Med Chem Lett 2015; 7(2): 172-6.
[http://dx.doi.org/10.1021/acsmedchemlett.5b00340] [PMID: 26985293]
Zhao YC, Xue CH, Zhang TT, Wang YM. Saponins from sea cucumber and their biological activities. J Agric Food Chem 2018; 66(28): 7222-37.
[http://dx.doi.org/10.1021/acs.jafc.8b01770] [PMID: 29932674]
Aminin DL, Agafonova IG, Berdyshev EV, Isachenko EG, Avilov SA, Stonik VA. Immunomodulatory properties of cucumariosides from the edible far-eastern holothurian Cucumaria japonica. J Med Food 2001; 4(3): 127-35.
[http://dx.doi.org/10.1089/109662001753165701] [PMID: 12639406]
Agafonova IG, Aminin DL, Avilov SA, Stonik VA. Influence of cucumariosides upon intracellular [Ca2+]i and lysosomal activity of macrophages. J Agric Food Chem 2003; 51(24): 6982-6.
[http://dx.doi.org/10.1021/jf034439x] [PMID: 14611158]
Aminin DL, Pinegin BV, Pichugina LV, et al. Immunomodulatory properties of Cumaside. Int Immunopharmacol 2006; 6(7): 1070-82.
[http://dx.doi.org/10.1016/j.intimp.2006.01.017] [PMID: 16714210]
Aminin DL, Gorpenchenko TY, Bulgakov VP, Andryjashchenko PV, Avilov SA, Kalinin VI. Triterpene glycoside cucumarioside A(2)-2 from sea cucumber stimulates mouse immune cell adhesion, spreading, and motility. J Med Food 2011; 14(6): 594-600.
[http://dx.doi.org/10.1089/jmf.2010.1274] [PMID: 21554137]
Pislyagin EA, Manzhulo IV, Dmitrenok PS, Aminin DL. Cucumarioside A2-2 causes changes in the morphology and proliferative activity in mouse spleen. Acta Histochem 2016; 118(4): 387-92.
[http://dx.doi.org/10.1016/j.acthis.2016.03.009] [PMID: 27079859]
Bahrami Y, Franco CM. Acetylated triterpene glycosides and their biological activity from Holothuroidea reported in the past six decades. Mar Drugs 2016; 14(8): 147.
[http://dx.doi.org/10.3390/md14080147] [PMID: 27527190]
Pislyagin EA, Manzhulo IV, Gorpenchenko TY, et al. Cucumarioside A2-2 causes macrophage activation in mouse spleen. Mar Drugs 2017; 15(11): 341.
[http://dx.doi.org/10.3390/md15110341] [PMID: 29104230]
Kicha AA, Kalinovsky AI, Malyarenko TV, et al. Cyclic steroid glycosides from the starfish Echinaster luzonicus: Structures and immunomodulatory activities. J Nat Prod 2015; 78(6): 1397-405.
[http://dx.doi.org/10.1021/acs.jnatprod.5b00332] [PMID: 26068600]
Einarsdottir E, Liu HB, Freysdottir J, Gotfredsen CH, Omarsdottir S. Immunomodulatory N-acyl dopamine glycosides from the icelandic marine sponge Myxilla incrustans collected at a hydrothermal vent site. Planta Med 2016; 82(9-10): 903-9.
[http://dx.doi.org/10.1055/s-0042-105877] [PMID: 27135626]
Sun YZ, Kurtán T, Mándi A, et al. Immunomodulatory polyketides from a phoma-like fungus isolated from a soft coral. J Nat Prod 2017; 80(11): 2930-40.
[http://dx.doi.org/10.1021/acs.jnatprod.7b00463] [PMID: 29048894]
Becker K, Hartmann A, Ganzera M, Fuchs D, Gostner JM. Immunomodulatory effects of the mycosporine-like amino acids Shinorine and Porphyra-334. Mar Drugs 2016; 14(6): 119.
[http://dx.doi.org/10.3390/md14060119] [PMID: 27338421]
Ye F, Li J, Wu Y, et al. Sarinfacetamides A and B, nitrogenous diterpenoids with tricyclo [,5] dodecane scaffold from the South China Sea soft coral Sarcophyton infundibuliforme. Org Lett 2018; 20(9): 2637-40.
[http://dx.doi.org/10.1021/acs.orglett.8b00842] [PMID: 29638136]
Kicha AA, Kalinovsky AI, Ivanchina NV, et al. Furostane series asterosaponins and other unusual steroid oligoglycosides from the tropical starfish Pentaceraster regulus. J Nat Prod 2017; 80(10): 2761-70.
[http://dx.doi.org/10.1021/acs.jnatprod.7b00574] [PMID: 28981263]
Gunasekera SP, Li Y, Ratnayake R, et al. Discovery, total synthesis and key structural elements for the immunosuppressive activity of cocosolide, a symmetrical glycosylated macrolide dimer from marine cyanobacteria. Chemistry 2016; 22(24): 8158-66.
[http://dx.doi.org/10.1002/chem.201600674] [PMID: 27139508]
Aiello A, Fattorusso E, Imperatore C, Menna M, Müller WE. Iodocionin, a cytotoxic iodinated metabolite from the Mediterranean ascidian Ciona edwardsii. Mar Drugs 2010; 8(2): 285-91.
[http://dx.doi.org/10.3390/md8020285] [PMID: 20390106]
Won TH, Kim CK, Lee SH, et al. Amino acid-derived metabolites from the ascidian Aplidium sp. Mar Drugs 2015; 13(6): 3836-48.
[http://dx.doi.org/10.3390/md13063836] [PMID: 26087023]
Đorđević MR, Radulović NS, Stojanović NM, Ranđelović PJ. Immunomodulatory activity of marine natural products: Synthesis, spectral characterization and toxicity assessment of natural and related synthetic iodinated tyramides. Food Chem Toxicol 2019; 125: 150-60.
[http://dx.doi.org/10.1016/j.fct.2018.12.039] [PMID: 30590140]
Luo M, Cui Z, Huang H, et al. Amino acid conjugated anthraquinones from the marine-derived fungus Penicillium sp. SCSIO sof101. J Nat Prod 2017; 80(5): 1668-73.
[http://dx.doi.org/10.1021/acs.jnatprod.7b00269] [PMID: 28509552]
Toledo TR, Dejani NN, Monnazzi LG, et al. Potent anti-inflammatory activity of pyrenocine A isolated from the marine-derived fungus Penicillium paxilli Ma(G)K. Mediators Inflamm 2014.2014767061
[http://dx.doi.org/10.1155/2014/767061] [PMID: 24574582]
Ali A, Khajuria A, Sidiq T, et al. Modulation of LPS induced inflammatory response by Lawsonyl monocyclic terpene from the marine derived Streptomyces sp. Immunol Lett 2013; 150(1-2): 79-86.
[http://dx.doi.org/10.1016/j.imlet.2012.09.001] [PMID: 22975588]
Villa FA, Lieske K, Gerwick L. Selective MyD88-dependent pathway inhibition by the cyanobacterial natural product malyngamide F acetate. Eur J Pharmacol 2010; 629(1-3): 140-6.
[http://dx.doi.org/10.1016/j.ejphar.2009.12.002] [PMID: 20006962]
Ye F, Zhu ZD, Chen JS, et al. Xishacorenes A-C, diterpenes with bicycle [3.3.1] nonane nucleus from the Xisha soft coral Sinularia polydactyla. Org Lett 2017; 19(16): 4183-6.
[http://dx.doi.org/10.1021/acs.orglett.7b01716] [PMID: 28762746]
Ciaglia E, Malfitano AM, Laezza C, et al. Immuno-modulatory and anti-inflammatory effects of dihydrogracilin A, a terpene derived from the marine sponge Dendrilla membranosa. Int J Mol Sci 2017; 18(8): 1643.
[http://dx.doi.org/10.3390/ijms18081643] [PMID: 28788056]
Lin CY, Lu MC, Su JH, et al. Immunomodulatory effect of marine cembrane-type diterpenoids on dendritic cells. Mar Drugs 2013; 11(4): 1336-50.
[http://dx.doi.org/10.3390/md11041336] [PMID: 23609581]
Gu BB, Wu WL, Li Y, et al. 3,5-Dimethylorsellinic acid derived meroterpenoids from Eupenicillium sp. 6A-9, a fungus isolated from the marine sponge Plakortis simplex. Eur J Org Chem 2018; 2018(1): 48-59.
Carbone M, Li Y, Irace C, et al. Structure and cytotoxicity of phidianidines A and B: First finding of 1,2,4-oxadiazole system in a marine natural product. Org Lett 2011; 13(10): 2516-9.
[http://dx.doi.org/10.1021/ol200234r] [PMID: 21506595]
Brogan JT, Stoops SL, Lindsley CW. Total synthesis and biological evaluation of phidianidines A and B uncovers unique pharmacological profiles at CNS targets. ACS Chem Neurosci 2012; 3(9): 658-64.
[http://dx.doi.org/10.1021/cn300064r] [PMID: 23019492]
Jiang CS, Fu Y, Zhang L, et al. Synthesis and biological evaluation of novel marine-derived indole-based 1,2,4-oxadiazoles derivatives as multifunctional neuroprotective agents. Bioorg Med Chem Lett 2015; 25(2): 216-20.
[http://dx.doi.org/10.1016/j.bmcl.2014.11.068] [PMID: 25499879]
Zhang L, Jiang CS, Gao LX, et al. Design, synthesis and in vitro activity of phidianidine B derivatives as novel PTP1B inhibitors with specific selectivity. Bioorg Med Chem Lett 2016; 26(3): 778-81.
[http://dx.doi.org/10.1016/j.bmcl.2015.12.097] [PMID: 26774579]
Li Z, Chen W, Hale JJ, et al. Discovery of potent 3,5-diphenyl-1,2,4-oxadiazole sphingosine-1-phosphate-1 (S1P1) receptor agonists with exceptional selectivity against S1P2 and S1P3. J Med Chem 2005; 48(20): 6169-73.
[http://dx.doi.org/10.1021/jm0503244] [PMID: 16190743]
Vu CB, Corpuz EG, Merry TJ, et al. Discovery of potent and selective SH2 inhibitors of the tyrosine kinase ZAP-70. J Med Chem 1999; 42(20): 4088-98.
[http://dx.doi.org/10.1021/jm990229t] [PMID: 10514279]
Liu J, Li H, Chen KX, et al. Design and synthesis of marine phidianidine derivatives as potential immunosuppressive agents. J Med Chem 2018; 61(24): 11298-308.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01430] [PMID: 30500185]
Martins LF, Mesquita JT, Pinto EG, et al. Analogues of marine guanidine alkaloids are in vitro effective against Trypanosoma cruzi and selectively eliminate Leishmania (L.) infantum intracellular amastigotes. J Nat Prod 2016; 79(9): 2202-10.
[http://dx.doi.org/10.1021/acs.jnatprod.6b00256] [PMID: 27586460]
Wang Q, Tang X, Luo X, de Voogd NJ, Li P, Li G. (+)- and (-)-Spiroreticulatine, A Pair of Unusual Spiro Bisheterocyclic Quinoline-imidazole Alkaloids from the South China Sea Sponge Fascaplysinopsis reticulata. Org Lett 2015; 17(14): 3458-61.
[http://dx.doi.org/10.1021/acs.orglett.5b01503] [PMID: 26126146]
Yang M, Liang LF, Li H, et al. A new 5α, 8α-epidioxysterol with immunosuppressive activity from the South China Sea soft coral Sinularia sp. Nat Prod Res 2019; 1-6.
Lee JY, Kim GJ, Choi JK, et al. 4- (hydroxymethyl) catechol extracted from fungi in marine sponges attenuates rheumatoid arthritis by inhibiting PI3K/Akt/NF-κB signaling. Front Pharmacol 2018; 9: 726.
[http://dx.doi.org/10.3389/fphar.2018.00726] [PMID: 30079020]

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Year: 2019
Page: [187 - 196]
Pages: 10
DOI: 10.2174/2212796813666190716102614

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