358
Views
5
CrossRef citations to date
0
Altmetric
Review

Novel approaches to glycomimetic design: development of small molecular weight lectin antagonists

, &
Pages 513-536 | Received 23 Jun 2020, Accepted 26 Nov 2020, Published online: 05 Feb 2021

References

  • Lis H, Sharon N. Lectins: carbohydrate-specific proteins that mediate cellular recognition. Chem Rev. 1998;98(2):637–674
  • Harjunpää H, Llort Asens M, Guenther C, et al. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment [Review]. Front Immunol. 2019;10(1078). doi:https://doi.org/10.3389/fimmu.2019.01078.English. .
  • Messinis IE, Messini CI, Daponte A, et al. The current situation of infertility services provision in Europe. Eur J Obstetrics Gynecol Reprod Biol. 2016;207:200–204.
  • Vicente-Manzanares M, Webb DJ, Horwitz AR. Cell migration at a glance. J Cell Sci. 2005;118(21):4917.
  • Zachary JF. Chapter 4 – mechanisms of microbial infections1. In: Zachary JF, editor. Pathologic basis of veterinary disease (Sixth Edition). Mosby: Elsevier; 2017. p. 132–241.e1.
  • Campbell BJ, Yu L-G, Rhodes JM. Altered glycosylation in inflammatory bowel disease: a possible role in cancer development. Glycoconj J. 2001;18(11):851–858.
  • Neufeld EF. Lysosomal storage diseases. Annu Rev Biochem. 1991;60(1):257–280.
  • Brown GD, Gordon S. A new receptor for β-glucans. Nature. 2001;413(6851):36–37.
  • Cobb B, Kasper D. Coming of age: carbohydrates and immunity. Eur J Immunol. 2005;02/01(35):352–356.
  • Gordon D. A critical difference between pathogenic and nonpathogenic bacteria. Gastroenterology. 2000;119(5):1188.
  • van Baarlen P, van Belkum A, Summerbell RC, et al. Molecular mechanisms of pathogenicity: how do pathogenic microorganisms develop cross-kingdom host jumps? FEMS Microbiol Rev. 2007;31(3):239–277.
  • Prydz K. Mammalian lectins and their relatives. J Cell Sci. 2001;114(13):2359.
  • Anderson K, Evers D, Rice KG. Structure and function of mammalian carbohydrate-lectin interactions. In: Fraser-Reid BO, Tatsuta K, Thiem J, editors. Glycoscience: chemistry and chemical biology. Berlin, Heidelberg: Springer Berlin Heidelberg; 2008. p. p. 2445–2482.
  • Li Z, Wang L, Lin X, et al. Drug delivery for bioactive polysaccharides to improve their drug-like properties and curative efficacy. Drug Deliv. 2017;24(2):70–80.
  • Ernst B, Magnani JL. From carbohydrate leads to glycomimetic drugs. Nat Rev Drug Discov. 2009; 8 (8): 661–677.
  • Hevey R. Strategies for the development of glycomimetic drug candidates. Pharmaceuticals. 2019;12(2):2.
  • Mydock-McGrane LK, Hannan TJ, Janetka JW. Rational design strategies for FimH antagonists: new drugs on the horizon for urinary tract infection and Crohn’s disease. Expert Opin Drug Discov. 2017; 12 (7): 711–731.
  • Chikalovets I, Filshtein A, Molchanova V, et al. Activity dependence of a novel lectin family on structure and carbohydrate-binding properties. Molecules. 2020;25:1.
  • Cecioni S, Imberty A, Vidal S. Glycomimetics versus multivalent glycoconjugates for the design of high affinity lectin ligands. Chem Rev. 2015;115(1):525–561.
  • Gabius H-J, André S, Jiménez-Barbero J, et al. From lectin structure to functional glycomics: principles of the sugar code. Trends Biochem Sci. 2011;36(6):298–313.
  • Mayer K, Eris D, Schwardt O, et al. Urinary tract infection: which conformation of the bacterial lectin FimH is therapeutically relevant. J Med Chem. 2017;60(13):5646–5662. . https://doi.org/doi:
  • Kleeb S, Jiang X, Frei P, et al. FimH antagonists: phosphate prodrugs improve oral bioavailability. J Med Chem. 2016;59(7):3163–3182.
  • Scharenberg M, Schwardt O, Rabbani S, et al. Target selectivity of FimH antagonists. J Med Chem. 2012;55(22):9810–9816.
  • Kleeb S, Pang L, Mayer K, et al. FimH antagonists: bioisosteres to improve the in vitro and in vivo PK/ PD profile. J Med Chem. 2015;58(5):2221–2239.
  • Han Z, Pinkner JS, Ford B, et al. Structure-based drug design and optimization of mannoside bacterial FimH antagonists. J Med Chem. 2010;53(12):4779–4792.
  • Mydock-McGrane L, Cusumano Z, Han Z et al. Antivirulence C-mannosides as antibiotic-sparing, oral therapeutics for urinary tract infections. J Med Chem. 2016;5920:9390–9408.
  • Han Z, Pinkner JS, Ford B, et al. Lead optimization studies on FimH antagonists: discovery of potent and orally bioavailable ortho-substituted biphenyl mannosides. J Med Chem. 2012;55(8):3945–3959.
  • Jarvis C, Han Z, Kalas V, et al. Antivirulence isoquinolone mannosides: optimization of the biaryl aglycone for FimH lectin binding affinity and efficacy in the treatment of chronic UTI. ChemMedChem. 2016;11(4):367–373.
  • Klein T, Abgottspon D, Wittwer M, et al. FimH antagonists for the oral treatment of urinary tract infections: from design and synthesis to in vitro and in vivo evaluation. J Med Chem. 2010;53(24):8627–8641.
  • Jiang X, Abgottspon D, Kleeb S, et al. Antiadhesion therapy for urinary tract infections – a balanced PK/PD profile proved to be key for success. J Med Chem. 2012;55(10):4700–4713.
  • Kalas V, Hibbing ME, Maddirala AR, et al. Structure-based discovery of glycomimetic FmlH ligands as inhibitors of bacterial adhesion during urinary tract infection. Proc Nat Acad Sci. 2018;115(12):E2819.
  • Maddirala AR, Klein R, Pinkner JS, et al. Biphenyl gal and galnac FmlH lectin antagonists of uropathogenic E. coli (UPEC): optimization through iterative rational drug design. J Med Chem. 2019;62(2):467–479.
  • von Itzstein M, Wu W-Y, Kok GB, et al. Rational design of potent sialidase-based inhibitors of influenza virus replication. Nature. 1993;363(6428):418–423.
  • Kim CU, Lew W, Williams MA, et al. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site: design, synthesis, and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity. J Am Chem Soc. 1997;119(4):681–690.
  • Weinreb NJ, Barranger JA, Charrow J, et al. Guidance on the use of miglustat for treating patients with type 1 Gaucher disease. Am J Hematol. 2005;80(3):223–229.
  • Campbell LK, Baker DE, Campbell RK. Miglitol: assessment of its role in the treatment of patients with diabetes mellitus. Ann Pharmacother. 2000;34(11):1291–1301. . PubMed PMID: 11098345; eng.
  • Xiaolong C, Yuguo Z, Yinchu S. Voglibose Basen®, AO-128), One of the most important α-glucosidase inhibitors. Curr Med Chem. 2006;13(1):109–116.
  • Truscheit E, Frommer W, Junge B, et al. Chemistry and biochemistry of microbial α-glucosidase inhibitors. Angew Chem Int Ed Engl. 1981;20(9):744–761.
  • Tentolouris A, Vlachakis P, Tzeravini E, et al. SGLT2 inhibitors: a review of their antidiabetic and cardioprotective effects. Int J Environ Res Public Health. 2019;16(16):2965.
  • Sharon N. Bacterial lectins, cell-cell recognition and infectious disease. FEBS Lett. 1987;217(2):145–157.
  • Kostakioti M, Hadjifrangiskou M, Hultgren SJ. Bacterial biofilms: development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era. Cold Spring Harb Perspect Med. 2013;3(4):a010306–a010306. . PubMed PMID: 23545571; eng
  • Friedman ND, Kaye KS, Stout JE, et al. Classifying types of bacterial infections. Ann Intern Med. 2002;137(10):1–36.
  • Sun F, Qu F, Ling Y, et al. Biofilm-associated infections: antibiotic resistance and novel therapeutic strategies. Future Microbiol. 2013;8(7):877–886.
  • Chopra I. The 2012 Garrod Lecture: discovery of antibacterial drugs in the 21st century. J Antimicrob Chemother. 2012;68(3):496–505.
  • Barondes SH, Cooper DNW, Gitt MA, et al. Galectins. Structure and function of a large family of animal lectins [Short Survey]. J Biol Chem. 1994;269(33):20807–20810.
  • Sarkar S, Hutton ML, Vagenas D, et al. Intestinal colonization traits of pandemic multidrug-resistant Escherichia coli ST131. J Infect Dis. 2018;218(6):979–990.
  • Schreiber HL, Conover MS, Chou W-C, et al. Bacterial virulence phenotypes of Escherichia coli and host susceptibility determine risk for urinary tract infections. Sci Transl Med. 2017;9(382):eaaf1283.
  • Wurpel DJ, Beatson SA, Totsika M, et al. Chaperone-usher fimbriae of Escherichia coli. PLoS One. 2013;8(1):e52835–e52835. . PubMed PMID: 23382825; eng
  • Hadjifrangiskou M, Hultgren SJ. What does it take to stick around? Molecular insights into biofilm formation by uropathogenic Escherichia coli. Virulence. 2012;3(3):231–233. . PubMed PMID: 22546905; eng.
  • Hartmann M, Lindhorst TK. The bacterial lectin FimH, a target for drug discovery – carbohydrate inhibitors of type 1 fimbriae-mediated bacterial adhesion. European J Org Chem. 2011;2011(20‐21):3583–3609.
  • Munera D, Hultgren S, Fernández LÁ. Recognition of the N-terminal lectin domain of FimH adhesin by the usher FimD is required for type 1 pilus biogenesis. Mol Microbiol. 2007;64(2):333–346.
  • Bouckaert J, Berglund J, Schembri M, et al. Receptor binding studies disclose a novel class of high-affinity inhibitors of the Escherichia coli FimH adhesin. Mol Microbiol. 2005;55(2):441–455.
  • Jones CH, Pinkner JS, Roth R, et al. FimH adhesin of type 1 pili is assembled into a fibrillar tip structure in the Enterobacteriaceae. Proc Nat Acad Sci. 1995;92(6):2081.
  • Busch A, Waksman G. Chaperone–usher pathways: diversity and pilus assembly mechanism. Philosophical Transactions of the Royal Society B. Biol Sci. 2012;367(1592):1112–1122.
  • Waksman G, Hultgren SJ. Structural biology of the chaperone–usher pathway of pilus biogenesis. Nature Rev Microbiol. 2009;7(11):765–774.
  • Sauer MM, Jakob RP, Eras J, et al. Catch-bond mechanism of the bacterial adhesin FimH. Nat Commun. 2016;7(1):10738.
  • Stahlhut SG, Tchesnokova V, Struve C, et al. Comparative structure-function analysis of mannose-specific FimH Adhesins from Klebsiella pneumoniae and Escherichia coli&gt. J Bacteriol. 2009;191(21):6592.
  • Phan G, Remaut H, Wang T, et al. Crystal structure of the FimD usher bound to its cognate FimC–FimH substrate. Nature. 2011;474(7349):49–53. . 2011/06/01
  • Kalas V, Pinkner JS, Hannan TJ, et al. Evolutionary fine-tuning of conformational ensembles in FimH during host-pathogen interactions. Sci Adv. 2017;3(2):e1601944.
  • Schwartz DJ, Kalas V, Pinkner JS, et al. Positively selected FimH residues enhance virulence during urinary tract infection by altering FimH conformation. Proc Nat Acad Sci. 2013;110(39):15530.
  • Spaulding CN, Klein RD, Ruer S, et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist. Nature. 2017;546(7659):528–532.
  • Spaulding CN, Kau AL, Klein RD, et al. Small-molecule inhibitors against type 1 pili selectively target uropathogenic E. coli in the gut and bladder. Faseb J. 2017;31(1_supplement):938.9–939.9.
  • Hung C-S, Bouckaert J, Hung D, et al. Structural basis of tropism of Escherichia coli to the bladder during urinary tract infection. Mol Microbiol. 2002;44(4):903–915.
  • Gouin SG, Wellens A, Bouckaert J, et al. Synthetic multimeric heptyl mannosides as potent antiadhesives of uropathogenic Escherichia coli. ChemMedChem. 2009;4(5):749–755.
  • Chandrasekaran V, Kolbe K, Beiroth F, et al. Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH. Beilstein J Org Chem. 2013;9:223–233. . PubMed PMID: 23399876; eng
  • Grabosch C, Hartmann M, Schmidt-Lassen J, et al. Squaric acid monoamide mannosides as ligands for the bacterial lectin FimH: covalent Inhibition or Not? ChemBioChem. 2011;12(7):1066–1074.
  • Beiroth F, Koudelka T, Overath T, et al. Diazirine-functionalized mannosides for photoaffinity labeling: trouble with FimH. Beilstein J Org Chem. 2018;07/24(14):1890–1900.
  • Hartmann M, Papavlassopoulos H, Chandrasekaran V, et al. Inhibition of bacterial adhesion to live human cells: activity and cytotoxicity of synthetic mannosides. FEBS Lett. 2012;586(10):1459–1465.
  • Lindhorst TK, Märten M, Fuchs A, et al. En route to photoaffinity labeling of the bacterial lectin FimH. Beilstein J Org Chem. 2010;6:810–822. . PubMed PMID: 20978617; eng
  • Scharenberg M, Schwardt O, Rabbani S, et al. Target selectivity of FimH antagonists. J Med Chem. 2012; 5522:9810–9816. . PubMed PMID: 23088608; eng.
  • Scharenberg M, Jiang X, Pang L, et al. Kinetic properties of carbohydrate-lectin interactions: FimH antagonists. ChemMedChem. 2014; 91:78–83. PubMed PMID: 24357503
  • Kleeb S, Jiang X, Frei P, et al. FimH antagonists: phosphate prodrugs improve oral bioavailability. J Med Chem. 2016; 597:3163–3182. . PubMed PMID: 26959338; eng.
  • Pang L, Kleeb S, Lemme K, et al. FimH antagonists: structure-activity and structure-property relationships for biphenyl α-D-mannopyranosides. ChemMedChem. 2012; 78:1404–1422. PubMed PMID: 22644941; eng.
  • Mydock-McGrane LK, Cusumano ZT, Janetka JW. Mannose-derived FimH antagonists: a promising anti-virulence therapeutic strategy for urinary tract infections and Crohn’s disease. Expert Opin Ther Pat. 2016;26(2):175–197.
  • Fimbrion and GSK to develop novel antibacterial therapy for urinary tract infections. 2016. [cited 2018 Dec 16]. Available from: https://www.fimbrion.com
  • Sperling O, Fuchs A, Lindhorst TK. Evaluation of the carbohydrate recognition domain of the bacterial adhesin FimH: design, synthesis and binding properties of mannoside ligands [10.1039/B610745A]. Org Biomol Chem. 2006;4(21):3913–3922.
  • Wurpel DJ, Totsika M, Allsopp LP, et al. F9 fimbriae of uropathogenic Escherichia coli are expressed at low temperature and recognise Galb1-3GlcNAc-containing glycans [Article]. PLoS One. 2014;9:3.
  • Conover Matt S, Ruer S, Taganna J, et al. Inflammation-induced adhesin-receptor interaction provides a fitness advantage to uropathogenic E. coli during chronic infection. Cell Host Microbe. 2016 ;20(4):482–492.
  • Dodson KW, Pinkner JS, Rose T et al. Structural basis of the interaction of the pyelonephritic E. coli adhesin to its human kidney receptor. Cell. 2001 ;1056:733–743.
  • Strömberg N, Nyholm PG, Pascher I, et al. Saccharide orientation at the cell surface affects glycolipid receptor function. Proc Nat Acad Sci. 1991;88(20):9340.
  • Johanson IM, Plos K, Marklund BI, et al. Pap, papG and prsG DNA sequences in Escherichia coli from the fecal flora and the urinary tract [Comparative Study Research Support, Non-U.S. Gov’t]. Microb Pathog. 1993; 152:121–129. . PubMed PMID: 7902954; eng.
  • Larsson A, Ohlsson J, Dodson KW, et al. Quantitative studies of the binding of the class II PapG adhesin from uropathogenic Escherichia coli to oligosaccharides. Bioorg Med Chem. 2003 ;11(10):2255–2261.
  • Ohlsson J, Jass J, Uhlin BE et al.Discovery of potent inhibitors of PapG adhesins from uropathogenic Escherichia coli through synthesis and evaluation of galabiose derivatives. Chembiochem Eur J Chem Biol. 2002 ;38:772–779.
  • Navarra G, Zihlmann P, Jakob RP, et a.. Carbohydrate-lectin interactions: an unexpected contribution to affinity. Chembiochem Eur J Chem Biol. 2017; 186:539–544. PubMed PMID: 28076665; eng.
  • de Bentzmann S, Plesiat P. The Pseudomonas aeruginosa opportunistic pathogen and human infections. Environ Microbiol. 2011;13(7):1655–1665. . PubMed PMID: 21450006; eng.
  • Gilboa-Garber N. Pseudomonas aeruginosa lectins. Methods Enzymol. 1982;83:378–385. . PubMed PMID: 6808301; eng
  • Imberty A, wimmerova M, Mitchell EP, et al. Structures of the lectins from Pseudomonas aeruginosa: insight into the molecular basis for host glycan recognition. Microbes Infect. 2004; 62:221–228. . PubMed PMID: 15049333.
  • Diggle SP, Stacey RE, Dodd C, et al. The galactophilic lectin, LecA, contributes to biofilm development in Pseudomonas aeruginosa. Environ Microbiol. 2006;8(6):1095–1104.
  • Tielker D, Hacker S, Loris R, et al. Pseudomonas aeruginosa lectin LecB is located in the outer membrane and is involved in biofilm formation. Microbiology. 2005;151(5):1313–1323.
  • Cioci G, Mitchell EP, Gautier C, et al. Structural basis of calcium and galactose recognition by the lectin PA-IL of Pseudomonas aeruginosa. FEBS Lett. 2003;555(2):297–301.
  • Wu L, Estrada O, Zaborina O, et al. Recognition of host immune activation by Pseudomonas aeruginosa. Science. 2005;309(5735):774–777.
  • Garber N, Guempel U, Belz A, et al. On the specificity of the d-galactose-binding lectin (PA-I) of Pseudomonas aeruginosa and its strong binding to hydrophobic derivatives of d-galactose and thiogalactose. Biochim Biophys Acta Gen Subj. 1992 ;1116(3):331–333.
  • Blanchard B, Nurisso A, Hollville E, et al. Structural basis of the preferential binding for globo-series glycosphingolipids displayed by Pseudomonas aeruginosa lectin I. J Mol Biol. 2008 ;383(4):837–853.
  • Eierhoff T, Bastian B, Thuenauer R, et al. A lipid zipper triggers bacterial invasion. Proc Nat Acad Sci. 2014;111(35):12895.
  • Joachim I, Rikker S, Hauck D, et al. Development and optimization of a competitive binding assay for the galactophilic low affinity lectin LecA from Pseudomonas aeruginosa. Org Biomol Chem. 2016; 1433:7933–7948. . PubMed PMID: 27488655; eng..
  • Palmioli A, Sperandeo P, Polissi A, et al. Targeting bacterial biofilm: a new LecA multivalent ligand with inhibitory activity. Chembiochem Eur J Chem Biol. 2019; 2023:2911–2915. PubMed PMID: 31216375.
  • Visini R, Jin X, Bergmann M, et al. Structural insight into multivalent galactoside binding to Pseudomonas aeruginosa lectin LecA. ACS Chem Biol. 2015;10(11):2455–2462.
  • Michaud G, Visini R, Bergmann M, et al. Overcoming antibiotic resistance in Pseudomonas aeruginosa biofilms using glycopeptide dendrimers [10.1039/C5SC03635F]. Chem Sci. 2016;7(1):166–182.
  • Boukerb AM, Rousset A, Galanos N, et al. Antiadhesive properties of glycoclusters against Pseudomonas aeruginosa lung infection. J Med Chem. 2014;57(24):10275–10289.
  • Kadam RU, Bergmann M, Hurley M, et al. A Glycopeptide dendrimer inhibitor of the galactose-specific lectin LecA and of Pseudomonas aeruginosa biofilms. Angew Chem Int Ed. 2011;50(45):10631–10635.
  • Ligeour C, Vidal O, Dupin L, et al. Mannose-centered aromatic galactoclusters inhibit the biofilm formation of Pseudomonas aeruginosa [10.1039/C5OB00948K]. Org Biomol Chem. 2015;13(31):8433–8444.
  • Malinovská L, Le S T, Herczeg M, et al. Synthesis of β-d-galactopyranoside-presenting glycoclusters, investigation of their interactions with Pseudomonas aeruginosa lectin A (PA-IL) and evaluation of their anti-adhesion potential. Biomolecules. 2019;9(11):686. . PubMed PMID: 31683947; eng
  • Pertici F, Pieters RJ. Potent divalent inhibitors with rigid glucose click spacers for Pseudomonas aeruginosa lectin LecA [10.1039/C2CC30234A]. Chem Commun. 2012;48(33):4008–4010. .
  • Yu G, Thies-Weesie DME, Pieters RJ. Tetravalent Pseudomonas aeruginosa adhesion lectin LecA inhibitor for enhanced biofilm inhibition. Helvetica Chimica Acta. 2019;102(3):e1900014.
  • Yu G, Vicini AC, Pieters RJ. Assembly of divalent ligands and their effect on divalent binding to Pseudomonas aeruginosa lectin LecA. J Org Chem. 2019;84(5):2470–2488.
  • Zahorska E, Kuhaudomlarp S, Minervini S, et al. A rapid synthesis of low-nanomolar divalent LecA inhibitors in four linear steps from d-galactose pentaacetate [10.1039/D0CC03490H]. Chem Commun. 2020;56(62):8822–8825.
  • Kadam RU, Garg D, Schwartz J et al. CH−π “T-shape” interaction with histidine explains binding of aromatic galactosides to Pseudomonas aeruginosa lectin LecA. ACS Chem Biol. 2013 ;89:1925–1930.
  • Wagner S, Hauck D, Hoffmann M, et al. Covalent lectin inhibition and application in bacterial biofilm imaging. Angew Chem Int Ed Engl. 2017;56(52):16559–16564. PubMed PMID: 28960731; eng.
  • Rodrigue J, Ganne G, Blanchard B, et al. Aromatic thioglycoside inhibitors against the virulence factor LecA from Pseudomonas aeruginosa [10.1039/C3OB41422A. Org Biomol Chem. 2013;11(40):6906–6918.
  • Mitchell E, Houles C, Sudakevitz D, et al. Structural basis for oligosaccharide-mediated adhesion of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients. Nat Struct Biol. 2002; 912:918–921. . PubMed PMID: 12415289; eng.
  • Perret S, Sabin C, Dumon C, et al. Structural basis for the interaction between human milk oligosaccharides and the bacterial lectin PA-IIL of Pseudomonas aeruginosa. Biochem J. 2005;389(2):325–332.
  • Sommer R, Wagner S, Varrot A, et al. The virulence factor LecB varies in clinical isolates: consequences for ligand binding and drug discovery [10.1039/C6SC00696E]. Chem Sci. 2016;7(8):4990–5001.
  • Boukerb AM, Decor A, Ribun S, et al. Genomic rearrangements and functional diversification of LecA and LecB lectin-coding regions impacting the efficacy of glycomimetics directed against Pseudomonas aeruginosa [Original Research]. Front Microbiol. 2016;7(811). doi:https://doi.org/10.3389/fmicb.2016.00811.English.
  • Meiers J, Siebs E, Zahorska E, et al. Lectin antagonists in infection, immunity, and inflammation. Curr Opin Chem Biol. 2019;53:51–67.
  • Cecioni S, Imberty A, Vidal S. Glycomimetics versus multivalent glycoconjugates for the design of high affinity lectin ligands. Chem Rev. 2015;115(1):525–561. . PubMed PMID: 25495138; eng.
  • Bernardi A, Jiménez-Barbero J, Casnati A, et al. Multivalent glycoconjugates as anti-pathogenic agents [10.1039/C2CS35408J]. Chem Soc Rev. 2013;42(11):4709–4727.
  • Andreini M, Anderluh M, Audfray A, et al. Monovalent and bivalent N-fucosyl amides as high affinity ligands for Pseudomonas aeruginosa PA-IIL lectin. Carbohydr Res. 2010;345(10):1400–1407.
  • Marotte K, Sabin C, Préville C et al. X-ray structures and thermodynamics of the interaction of PA-IIL from Pseudomonas aeruginosa with disaccharide derivatives. ChemMedChem. 2007 ;29:1328–1338.
  • Cecioni S, Faure S, Darbost U, et al. Selectivity among two lectins: probing the effect of topology, multivalency and flexibility of “Clicked” Multivalent Glycoclusters. Chemistry - A European Journal. 2011;17(7):2146–2159.
  • Hauck D, Joachim I, Frommeyer B, et al. Discovery of two classes of potent glycomimetic inhibitors of Pseudomonas aeruginosa LecB with distinct binding modes. ACS Chem Biol. 2013;8(8):1775–1784.
  • Sommer R, Hauck D, Varrot A, et al. Cinnamide derivatives of d-mannose as inhibitors of the bacterial virulence factor LecB from Pseudomonas aeruginosa. ChemistryOpen. 2015;4(6):756–767.
  • Sommer R, Wagner S, Rox K, et al. Glycomimetic, orally bioavailable LecB inhibitors block biofilm formation of Pseudomonas aeruginosa. J Am Chem Soc. 2018 ;1407:2537–2545.
  • Sommer R, Rox K, Wagner S, et al. Anti-biofilm agents against Pseudomonas aeruginosa: a structure–activity relationship study of C-glycosidic LecB inhibitors. J Med Chem. 2019;62(20):9201–9216.
  • Fan E, Merritt EA, Verlinde CLMJ, et al. AB5 toxins: structures and inhibitor design. Curr Opin Struct Biol. 2000 ;10(6):680–686.
  • Beddoe T, Paton AW, Le Nours J, et al. Structure, biological functions and applications of the AB5 toxins. Trends Biochem Sci. 2010 ;35(7):411–418.
  • Cervin J, Wands AM, Casselbrant A, et al. GM1 ganglioside-independent intoxication by Cholera toxin. PLoS Pathog. 2018;14(2):e1006862.
  • Kumar V, Turnbull WB. Carbohydrate inhibitors of cholera toxin. Beilstein J Org Chem. 2018;14:484–498.
  • Mattarella M, Garcia-Hartjes J, Wennekes T, et al. Nanomolar cholera toxin inhibitors based on symmetrical pentavalent ganglioside GM1os-sym-corannulenes [10.1039/C3OB40438B]Org& Bio Chemi. 2013;11(26):4333–4339.
  • Garcia-Hartjes J, Bernardi S, Weijers CAGM, et al. Picomolar inhibition of cholera toxin by a pentavalent ganglioside GM1os-calix[5]arene [10.1039/C3OB40515J]. Org Biomol Chem. 2013;11(26):4340–4349.
  • Pickens JC, Merritt EA, Ahn M, et al. Anchor-based design of improved cholera toxin and E. coli heat-labile enterotoxin receptor binding antagonists that display multiple binding modes. Chem Biol. 2002 ;9(2):215–224.
  • Kitov PI, Sadowska JM, Mulvey G, et al. Shiga-like toxins are neutralized by tailored multivalent carbohydrate ligands. Nature. 2000;403(6770):669–672.
  • Mulvey GL, Marcato P, Kitov PI, et al. Assessment in mice of the therapeutic potential of tailored, multivalent shiga toxin carbohydrate Ligands. J Infect Dis. 2003;187(4):640–649.
  • Kitov PI, Mulvey GL, Griener TP, et al. In vivo supramolecular templating enhances the activity of multivalent ligands: a potential therapeutic against the Escherichia coli O157 AB5 toxins. Proc Nat Acad Sci. 2008;105(44):16837.
  • O’Reilly MK, Collins BE, Han S, et al. Bifunctional CD22 ligands use multimeric immunoglobulins as protein scaffolds in assembly of immune complexes on B cells. J Am Chem Soc. 2008;130(24):7736–7745.
  • Kanda V, Kitov P, Bundle DR, et al. Surface plasmon resonance imaging measurements of the inhibition of shiga-like toxin by synthetic multivalent inhibitors. Anal Chem. 2005;77(23):7497–7504.
  • Nishikawa K, Matsuoka K, Kita E, et al. A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7 [Article]. Proc Natl Acad Sci U S A. 2002;99(11):7669–7674.
  • Watanabe-Takahashi M, Sato T, Dohi T, et al. An orally applicable shiga toxin neutralizer functions in the intestine to inhibit the intracellular transport of the toxin. Infect Immun. 2010;78(1):177.
  • Solomon D, Kitov PI, Paszkiewicz E, et al. Heterobifunctional multivalent inhibitor-adaptor mediates specific aggregation between Shiga toxin and a pentraxin. Org Lett. 2005;7(20):4369–4372.
  • Nishikawa K, Watanabe M, Kita E, et al. A multivalent peptide library approach identifies a novel Shiga toxin inhibitor that induces aberrant cellular transport of the toxin. Faseb J. 2006;2014:2597–2599.
  • Debnath A, Rodriguez MA, Ankri S. Editorial: recent Progresses in amebiasis [Editorial]. Front Cell Infect Microbiol. 2019 ;9247: 10.3389/fcimb.2019.00247. English https://doi.org/10.3389/fcimb.2019.00247
  • Frederick JR, Petri WA Jr.. Roles for the galactose-/N-acetylgalactosamine-binding lectin of Entamoeba in parasite virulence and differentiation. Glycobiology. 2005;15(12):53R–59R.
  • Boettner DR, Huston C, Petri WA. Galactose/N-acetylgalactosamine lectin: the coordinator of host cell killing. J Biosci. 2002;27(6):553–557.
  • Barroso L, Abhyankar M, Noor Z, et al. Expression, purification, and evaluation of recombinant LecA as a candidate for an amebic colitis vaccine. Vaccine. 2014; 3210:1218–1224. PubMed PMID: 23827311; PubMed Central PMCID: PMCPMC3883878. eng.
  • Adler P, Wood SJ, Lee YC, et al.. High affinity binding of the Entamoeba histolytica lectin to polyvalent N-acetylgalactosaminides. J Biol Chem. 1995;270(10):5164–5171.
  • Crocker PR, Paulson JC, Varki A. Siglecs and their roles in the immune system. Nat Rev Immunol. 2007;7(4):255–266.
  • Lopez-Lucendo MF, Solis D, Andre S, et al.. Growth-regulatory human galectin-1: crystallographic characterisation of the structural changes induced by single-site mutations and their impact on the thermodynamics of ligand binding. J Mol Biol. 2004; 3434:957–970. PubMed PMID: 15476813; eng.
  • Geijtenbeek TB, van Kooyk YDC. SIGN: a novel HIV receptor on DCs that mediates HIV-1 transmission. Curr Top Microbiol Immunol. 2003;276:31–54. PubMed PMID: 12797442; eng.
  • Geijtenbeek TB, Torensma R, van Vliet SJ, et al. Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell. 2000; 1005:575–585. PubMed PMID: 10721994; eng.
  • Lipsick JS, Beyer EC, Barondes SH, et al.. Lectins from chicken tissues are mitogenic for Thy-1 negative murine spleen cells. Biochem Biophys Res Commun. 1980; 971:56–61. PubMed PMID: 7458941; eng.
  • Rabinovich GA. Galectin-1 as a potential cancer target. Br J Cancer. 2005;92(7):1188–1192.
  • Califice S, Castronovo V, Van Den Brule F. Galectin-3 and cancer (Review). Int J Oncol. 2004;25 4:983–992. PubMed PMID: 15375548; eng .
  • Dumic J, Dabelic S, Flögel M. Galectin-3: an open-ended story. Biochim Biophys Acta Gen Subj. 2006 ;1760(4):616–635.
  • Sharma UC, Pokharel S, Van Brakel TJ, et al. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction [Article]. Circulation. 2004;110(19):3121–3128.
  • Raimond J, Zimonjic DB, Mignon C, et al. Mapping of the galectin-3 gene (LGALS3) to human chromosome 14 at region 14q21-22 [Article]. Mammalian Genome. 1997;8(9):706–707.
  • van Hattum H, Branderhorst HM, Moret EE, et al. Tuning the preference of thiodigalactoside- and lactosamine-based ligands to galectin-3 over galectin-1. J Med Chem. 2013; 563:1350–1354. . PubMed PMID: 23281927; eng.
  • Peterson K, Kumar R, Stenström O, et al. Systematic tuning of fluoro-galectin-3 interactions provides thiodigalactoside derivatives with single-digit nM affinity and high selectivity. J Med Chem. 2018 ;613:1164–1175.
  • Rajput VK, MacKinnon A, Mandal S, et al. A selective galactose–coumarin-derived galectin-3 inhibitor demonstrates involvement of galectin-3-glycan interactions in a pulmonary fibrosis model. J Med Chem. 2016;59(17):8141–8147.
  • Delaine T, Collins P, MacKinnon A, et al. Galectin-3-binding glycomimetics that strongly reduce bleomycin-induced lung fibrosis and modulate intracellular glycan recognition. ChemBioChem. 2016;17(18):1759–1770.
  • Chen* W-S, Cao Z, Leffler H, et al. Galectin-3 inhibition by a small-molecule inhibitor reduces both pathological corneal neovascularization and fibrosis. Invest Ophthalmol Vis Sci. 2017;58(1):9–20.
  • A study to test the efficacy and safety of inhaled TD139 in subjects with idiopathic pulmonary fibrosis (IPF) 2019. [cited 2019 February 6]. Available from: https://clinicaltrials.gov/
  • Fernández-Tejada A, Cañada FJ, Jiménez-Barbero J. Recent developments in synthetic carbohydrate-based diagnostics, vaccines, and therapeutics. Chem Eur J. 2015;21(30):10616–10628.
  • Zetterberg FR, Peterson K, Johnsson RE, et al. Monosaccharide derivatives with low-nanomolar lectin affinity and high selectivity based on combined fluorine–amide, phenyl–arginine, sulfur–π, and halogen bond interactions [Article]. ChemMedChem. 2018;13(2):133–137.
  • Van Liempt E, Imberty A, Bank CMC, et al. Molecular basis of the differences in binding properties of the highly related C-type lectins DC-SIGN and L-SIGN to Lewis X Trisaccharide and Schistosoma mansoni Egg Antigens [10.1074/jbc.M404988200]. J Biol Chem. 2004;279(32):33161–33167.
  • Drickamer K, Taylor ME. Recent insights into structures and functions of C-type lectins in the immune system. Curr Opin Struct Biol. 2015 ;34:26–34.
  • Geijtenbeek TBH, van Kooyk Y. DC-SIGN: A novel HIV receptor on DCs that mediates HIV-1 transmission. In: Steinkasserer A, editor. Dendritic cells and virus infection. Berlin, Heidelberg: Springer Berlin Heidelberg; 2003. p. 31–54.
  • Dam TK, Brewer CF. Lectins as pattern recognition molecules: the effects of epitope density in innate immunity*. Glycobiology. 2009;20(3):270–279.
  • Lasala F, Arce E, Otero JR, et al. Mannosyl glycodendritic structure inhibits DC-SIGN-mediated Ebola virus infection in cis and in trans. Antimicrob Agents Chemother. 2003 Dec;47(12):3970–3972. PubMed PMID: 14638512; PubMed Central PMCID: PMCPMC296220. eng.
  • Bertolotti B, Sutkeviciute I, Ambrosini M, et al. Polyvalent C-glycomimetics based on l-fucose or d-mannose as potent DC-SIGN antagonists [10.1039/C7OB00322F]. Org Biomol Chem. 2017;15(18):3995–4004.
  • Porkolab V, Chabrol E, Varga N, et al. Rational-differential design of highly specific glycomimetic ligands: targeting dc-sign and excluding langerin recognition. ACS Chem Biol. 2018 ;133:600–608.
  • Aretz J, Baukmann H, Shanina E, et al. Identification of multiple druggable secondary sites by fragment screening against DC-SIGN.Ang Chemie. 2017 ;5625:7292–7296
  • Kansas GS, Saunders KB, Ley K, et al. A role for the epidermal growth factor-like domain of P-selectin in ligand recognition and cell adhesion. J Cell Biol. 1994;124(4):609–618.
  • Ley K. The role of selectins in inflammation and disease. Trends Mol Med. 2003 ;9(6):263–268.
  • Berg EL, Robinson MK, Mansson O, et al. A carbohydrate domain common to both sialyl Le(a) and sialyl Le(X) is recognized by the endothelial cell leukocyte adhesion molecule ELAM-1. J Biol Chem PubMed PMID: 1714447; eng. 1991 ;266(23): 14869–14872.
  • Poppe L, Brown GS, Philo JS, et al. Conformation of sLex Tetrasaccharide, Free in Solution and Bound to E-, P-, and L-Selectin. J Am Chem Soc. 1997;119(7):1727–1736.
  • Egger J, Weckerle C, Cutting B, et al. Nanomolar E-selectin antagonists with prolonged half-lives by a fragment-based approach. J Am Chem Soc. 2013;135(26):9820–9828.
  • Peters T, Scheffler K, Ernst B, et al. Determination of the bioactive conformation of the carbohydrate ligand in the E‐Selectin/Sialyl LewisX Complex [Article]. Angew Chem Int Ed Engl. 1995;34(17):1841–1844.
  • Thoma G, Magnani JL, Patton JT, et al. Preorganization of the bioactive conformation of sialyl LewisX analogues correlates with their affinity to E-selectin [Article].Angewandte Chemie - Inter Edi. 2001;40(10):1941–1945.
  • Schwizer D, Patton JT, Cutting B, et al. Pre-organization of the core structure of E-selectin antagonists. Chemistry–A Europ Jourl. 2012 ;185:1342–1351.
  • Chang J, Patton JT, Sarkar A, et al. GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood. 2010;116(10):1779–1786.
  • Norman KE, Anderson GP, Kolb HC, et al. Sialyl Lewis(x) (sLe(x)) and an sLe(x) mimetic, CGP69669A, disrupt E- selectin-dependent leukocyte rolling in vivo [Article]. Blood. 1998;91(2):475–483.
  • Efficacy and safety of Rivipansel (GMI-1070) in the treatment of vaso-occlusive crisis in hospitalized subjects with sickle cell disease 2014. [cited 2014 June 12]. Available from: https://clinicaltrials.gov/ct2/show/record/NCT02187003
  • Schnaar RL, Lopez PH. Myelin-associated glycoprotein and its axonal receptors. J Neurosci Res. 2009;87(15):3267–3276. PubMed PMID: 19156870; PubMed Central PMCID: PMCPMC2892843. eng.
  • Lopez PHH. Role of myelin-associated glycoprotein (Siglec-4a) in the nervous system. In: Yu RK, Schengrund C-L, editors. Glycobiology of the nervous system. New York NY: Springer New York; 2014. p. 245–262.
  • Schnaar RL, Collins BE, Wright LP, et al. Myelin-associated glycoprotein binding to gangliosides. Structural specificity and functional implications. Ann N Y Acad Sci. 1998;845:92–105. PubMed PMID: 9668345; eng
  • Angata T, Nycholat CM, Macauley MS. Therapeutic targeting of siglecs using antibody- and glycan-based approaches. Trends Pharmacol Sci. 2015;36(10):645–660.
  • O’Reilly MK, Paulson JC. Siglecs as targets for therapy in immune-cell-mediated disease. Trends Pharmacol Sci. 2009;30(5):240–248.
  • Schwardt O, Kelm S, Ernst B. SIGLEC-4 (MAG) antagonists: from the natural carbohydrate epitope to glycomimetics. In: Gerardy-Schahn R, Delannoy P, von Itzstein M, editors. SialoGlyco chemistry and biology II: tools and Techniques to identify and capture sialoglycans. Cham: Springer International Publishing; 2015. p. 151–200.
  • Zaccai NR, Maenaka K, Maenaka T, et al. Structure-guided design of sialic acid-based siglec inhibitors and crystallographic analysis in complex with sialoadhesin. Structure. 2003 ;11(5):557–567.
  • Macauley MS, Crocker PR, Paulson JC. Siglec-mediated regulation of immune cell function in disease. Nat Rev Immunol. 2014;14(10):653–666.
  • Prescher H, Schweizer A, Kuhfeldt E, et al. Discovery of multifold modified sialosides as human CD22/Siglec-2 ligands with nanomolar activity on B-cells. ACS Chem Biol. 2014 ;97:1444–1450.
  • Peng W, Paulson JC. CD22 ligands on a natural N-glycan scaffold efficiently deliver toxins to B-lymphoma cells. J Am Chem Soc. 2017;139(36):12450–12458.
  • A study of a FimH blocker, EB8018, in Crohn’s disease patients (EBFIM117) 2018. [cited 2018 Apr 11]. Available from: https://clinicaltrials.gov/ct2/show/NCT03709628

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.