From carbohydrate leads to glycomimetic drugs

Ernst, Beat; Magnani, John L.

doi:10.1038/nrd2852

Cited by 716 publications

(623 citation statements)

References 193 publications

(144 reference statements)

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“…However, the fact that lectins display moderate affinities to their ligands renders this class of proteins as difficult targets for drugs 2. Despite this drawback, a number of recent success stories impressively demonstrated their potential for therapy: the selectin antagonist GMI‐1070 is currently in phase III clinical trials, and various FimH inhibitors are in the late preclinical stage 2, 3…”

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confidence: 99%

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

et al. 2017

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Biofilm formation by pathogenic bacteria is a hallmark of chronic infections. In many cases, lectins play key roles in establishing biofilms. The pathogen Pseudomonas aeruginosa often exhibiting various drug resistances employs its lectins LecA and LecB as virulence factors and biofilm building blocks. Therefore, inhibition of the function of these proteins is thought to have potential in developing “pathoblockers” preventing biofilm formation and virulence. A covalent lectin inhibitor specific to a carbohydrate binding site is described for the first time. Its application in the LecA‐specific in vitro imaging of biofilms formed by P. aeruginosa is also reported.

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confidence: 99%

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

et al. 2017

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“…[16] Simultaneously, the development of more potent FimH antagonists followed two major directions. First, multivalent FimH antagonists were investigated [33] and second, based on structural information obtained from the crystal structure of FimH co-crystallized with antagonists, [34] monovalent, high-affinity antagonists were designed [27] (the design, synthesis and in vitro evaluation of mono-and oligovalent mannosides is reviewed in detail by Hartmann and Lindhorst, [27] and Ernst and Magnani [35] ).…”

Section: Upia Type 1pilimentioning

confidence: 99%

In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

Abgottspon¹,

Ernst

2012

Chimia

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The discovery of antimicrobials as β-lactam antibiotics or aminoglycosides revolutionized the treatment of infectious diseases. However, the extensive use rapidly created the problem of resistant pathogens, which are increasingly difficult to treat. FimH antagonists are a new class of antimicrobials, which target the bacterial adhesion to urothelial cells, a crucial first step in the establishment of urinary tract infections. Because of their different mode of action, FimH antagonists neither kill nor inhibit the growth of bacteria, they should have a reduced potential to generate resistant strains. This mini-review outlines the main problems associated with increasing development of antimicrobial resistance. Furthermore, it summarizes the currently available in vivo studies in mice for the treatment of urinary tract infections conducted with FimH antagonists.

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“…1 Glycomimetics resemble natural carbohydrates in their structure and/or biological function and often serve as lead compounds for drug design. 2 One of the most important features of such compounds is the hydrolytic stability of the bond(s), which replace the natural O-glycosidic linkage(s). A wide range of such replacements were suggested, among others S-glycosides and C-glycosyl derivatives with a sulfur atom or a methylene group, respectively, in the position of the glycosidic oxygen.…”

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Photoinitiated hydrothiolation of pyranoid exo-glycals: the d-galacto and d-xylo cases

József

Juhász

Illyés

et al. 2015

Carbohydrate Research

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Exclusive regio-and stereoselectivity with exo-galactal. Exclusive regio-and very high stereoselectivity with exo-xylal. Disaccharide mimicks of Gly-CH 2 -S-Gly scaffolds. Contents lists available at ScienceDirectCarbohydrate Research j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m/ l o c a t e / c a r r e s a b s t r a c tRadical-mediated addition reactions of thiols to O-peracetylated exo-galactal and exo-xylal with 2,2-dimethoxy-2-phenylacetophenone as the photoinitiator resulted in high yielding formation of the corresponding b-D-glycopyranosylmethyl-sulfide derivatives (2,6-anhydro-1-deoxy-1-S-substituted-1-thioalditols) with exclusive regio-and very high stereoselectivity, including disaccharide mimicks with Gly-CH 2 -S-Gly scaffolds. © 2015 Published by Elsevier Ltd.Glycomimetic compounds are widely used for deciphering the biological roles of carbohydrate derivatives.1 Glycomimetics resemble natural carbohydrates in their structure and/or biological function and often serve as lead compounds for drug design. 2 One of the most important features of such compounds is the hydrolytic stability of the bond(s), which replace the natural O-glycosidic linkage(s). A wide range of such replacements were suggested, among others S-glycosides and C-glycosyl derivatives with a sulfur atom or a methylene group, respectively, in the position of the glycosidic oxygen. 1 In addition, in a number of examples two (or even more) atoms are inserted between the glycon and aglycon 3 in the form of e.g., SeS, 4e8 SeSe, 8e10 SO 2 eN, 11e13 NeC(¼O)eN linking moieties. 14e17Carbohydrate derivatives displaying Gly-CH 2 -S-R scaffolds are much less represented among glycomimetics although some synthetic methods, mostly limited to the application of O-perbenzylated exo-glycals, can be found in the literature. Thus, exo-glucal was transformed in several steps into a Glc-CH 2 -I derivative, 18e20 which was reacted under basic conditions with aliphatic and aromatic thiols including sugar derivatives to give the above structures. Ring openings by nucleophiles of an exo-glucal-derived spiro-epoxide 21 as well as a spiro-episulfonium ion 22 resulted in ulose derivatives featuring the above structure. Radical-mediated addition of AcSH to exo-glycals furnished S-(b-D-glycosylmethyl) thioacetates. 23The thiol-ene addition chemistry, 24,25 either in ionic or radicalmediated versions, has found several applications in carbohydrate chemistry for S-glycoconjugation, wherein the sugar derivative generally plays the role of the thiol or is functionalized by O-or Cappended unsaturated moieties. 26 Much less work has been devoted to additions of thiols to sugar 'ene'-s in which the double bond is part of or directly attached to the sugar ring: thus, additions to sugar derived enones 27 and some reactions of endo28e30 and recently also exo-glycals 30e33 as well as derivatives with an exomethylene group in the 4-and a 5-position of a furanoside and a pyranoside, 34 respectively, and a 3-exomethylene-glucofuranose 31,32 have been report...

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From carbohydrate leads to glycomimetic drugs

Cited by 716 publications

References 193 publications

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

Covalent Lectin Inhibition and Application in Bacterial Biofilm Imaging

In vivo Evaluation of FimH Antagonists – A Novel Class of Antimicrobials for the Treatment of Urinary Tract Infection

Photoinitiated hydrothiolation of pyranoid exo-glycals: the d-galacto and d-xylo cases

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