“Double‐Click” Protocol for Synthesis of Heterobifunctional Multivalent Ligands: Toward a Focused Library of Specific Norovirus Inhibitors

Guiard, Julie; Fiege, Brigitte; Kitov, Pavel I.; Peters, Thomas; Bundle, David R.

doi:10.1002/chem.201003414

Cited by 28 publications

(27 citation statements)

References 23 publications

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“…[26] From crystallographic data we have identified two main distances of 25 or 75 between HBGA binding sites (cf. Figure 3).…”

Section: Wwwchemeurjorg Discussionmentioning

confidence: 99%

“…For P2, where compound 160 and a-l-fucose are attached to the same propionylamide residues of the polymer, a reduction of the IC 50 value by a factor of almost 10 6 is observed. The assay has also been used to measure the avidity of polymeric inhibitors related to P1 and P2 in reference [26]. All binding curves are shown in the Supporting Information of that paper and that study also includes data from a homogeneous assay based on STD NMR titrations that correlate well with the Biacore data.…”

Section: Wwwchemeurjorgmentioning

confidence: 98%

“…The distance between binding sites on a dimer is approximately 25 , and distances of approximately 75 are found to the next dimeric units ( Figure 3). To obtain high avidity ligands we synthesized multivalent polymers (see accompanying paper of Guiard et al [26] ) that can position single fucose residues or compounds at distances found in the crystallographic study of Norwalk VLP. The drawing is based on the crystal structure of the prototype Norwalk virus [8] (pdb code: 1ihm).…”

Section: Synthesis Of Multivalent Inhibitorsmentioning

confidence: 99%

“…The synthesis of P1 and P2 and related polymers is described in an accompanying paper. [26] Binding studies with surface plasmon resonance-Biacorebased binding assay: To obtain data on the binding affinity of HBGA ligands and to establish a binding assay that allows ranking of potential NV entry inhibitors, we performed surface plasmon resonance experiments. We applied a setup where an a-l-fucopyranoside linked to a polymeric backbone and labeled with biotin (a-l-fucopyranosyl-PAAbiotin) had been immobilized to a C1 chip through noncovalent neutravidin-biotin interactions.…”

Section: Wwwchemeurjorgmentioning

confidence: 99%

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Targeting Norovirus Infection—Multivalent Entry Inhibitor Design Based on NMR Experiments

Rademacher

Guiard

Kitov

et al. 2011

Chemistry A European J

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Noroviruses attach to their host cells through histo blood group antigens (HBGAs), and compounds that interfere with this interaction are likely to be of therapeutic or diagnostic interest. It is shown that NMR binding studies can simultaneously identify and differentiate the site for binding HBGA ligands and complementary ligands from a large compound library, thereby facilitating the design of potent heterobifunctional ligands. Saturation transfer difference (STD) NMR experiments, spin-lock filtered NMR experiments, and interligand NOE (ILOE) experiments in the presence of virus-like particles (VLPs), identified compounds that bind to the HBGA binding site of human norovirus. Based on these data two multivalent prototype entry-inhibitors against norovirus infection were synthesized. A surface plasmon resonance based inhibition assay showed avidity gains of 1000 and one million fold over a millimolar univalent ligand. This suggests that further rational design of multivalent inhibitors based on our strategy will identify potent entry-inhibitors against norovirus infections.

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“…[26] From crystallographic data we have identified two main distances of 25 or 75 between HBGA binding sites (cf. Figure 3).…”

Section: Wwwchemeurjorg Discussionmentioning

confidence: 99%

Section: Wwwchemeurjorgmentioning

confidence: 98%

Section: Synthesis Of Multivalent Inhibitorsmentioning

confidence: 99%

Section: Wwwchemeurjorgmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Norovirus Infection—Multivalent Entry Inhibitor Design Based on NMR Experiments

Rademacher

Guiard

Kitov

et al. 2011

Chemistry A European J

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“…Two multivalent prototype entry-inhibitors against norovirus infection were synthesized with IC 50 values of ~ 80 μM (compound ID 16 ) and 0.61 μM (compound ID 17 ) as measured using competitive surface plasmon resonance (Supplementary Table 2). Some hetero-bifunctional ligands were also synthesized on a polymeric scaffold to determine the effect of multivalency on binding avidity and demonstrated, by competitive SPR and STD-titration experiments, to have significant inhibitory activities against norovirus VLPs (compounds ID from 44 to 47 ) (Guiard et al, 2011) (Supplementary Table 2). Moreover, citrate, having a high degree of mimicry to fucose, may have the potential to block human noroviruses from binding to HBGAs (Hansman et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens

et al. 2016

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Human noroviruses are the leading causative agents of epidemic and sporadic viral gastroenteritis and childhood diarrhoea worldwide. Human histo-blood group antigens (HBGA) serve as receptors for norovirus capsid protein attachment and play a critical role in infection. This makes HBGA-norovirus binding a promising target for drug development. Recently solved crystal structures of norovirus bound to HBGA have provided a structural basis for identification of potential anti-norovirus drugs and subsequently performed in silico and in vitro drug screens have identified compounds that block norovirus binding and may thereby serve as structural templates for design of therapeutic norovirus inhibitors. This review explores norovirus therapeutic options based on the strategy of blocking norovirus-HBGA binding.

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Attachment of Norovirus to Histo Blood Group Antigens: A Cooperative Multistep Process

et al. 2015

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Human noroviruses recognizeh isto blood group antigens (HBGAs) as cellular attachment factors.R ecently,i t has been discovered that norovirus infection can be significantly enhanced by HBGA binding.Yet the attachment process and howitpromotes host-cell entry is only poorly understood. The binding of an orovirus protruding (P) domain of ap redominant GII.4 Saga strain to HBGAs at atomic resolution was studied. So far,i ndependent and equivalent multiple binding sites were held responsible for attachment. Using NMR experiments we show that norovirus-HBGA binding is ac ooperative multi-step process,a nd native mass spectrometry reveals four instead of two HBGA binding sites per P-dimer.A na ccompanying crystallographic study has disclosed four instead of two l-fucose binding sites per Pdimer of ar elated GII.10 strain [1] further supporting our findings.W eh ave uncovered anovel paradigm for norovirus-HBGA recognition that will inspire further studies into norovirus-host interactions.

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“Double‐Click” Protocol for Synthesis of Heterobifunctional Multivalent Ligands: Toward a Focused Library of Specific Norovirus Inhibitors

Cited by 28 publications

References 23 publications

Targeting Norovirus Infection—Multivalent Entry Inhibitor Design Based on NMR Experiments

Targeting Norovirus Infection—Multivalent Entry Inhibitor Design Based on NMR Experiments

Norovirus drug candidates that inhibit viral capsid attachment to human histo-blood group antigens

Attachment of Norovirus to Histo Blood Group Antigens: A Cooperative Multistep Process

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