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1.
J Biol Chem ; 289(2): 885-94, 2014 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-24225957

RESUMO

Shiga toxin type 2 (Stx2a) is clinically most closely associated with enterohemorrhagic E. coli O157:H7-mediated hemorrhagic colitis that sometimes progresses to hemolytic-uremic syndrome. The ability to express the toxin has been acquired by other Escherichia coli strains, and outbreaks of food poisoning have caused significant mortality rates as, for example, in the 2011 outbreak in northern Germany. Stx2a, an AB5 toxin, gains entry into human cells via the glycosphingolipid receptor Gb3. We have determined the first crystal structure of a disaccharide analog of Gb3 bound to the B5 pentamer of Stx2a holotoxin. In this Gb3 analog,-GalNAc replaces the terminal-Gal residue. This co-crystal structure confirms previous inferences that two of the primary binding sites identified in theB5 pentamer of Stx1 are also functional in Stx2a. This knowledge provides a rationale for the synthesis and evaluation of heterobifunctional antagonists for E. coli toxins that target Stx2a. Incorporation of GalNAc Gb3 trisaccharide in a heterobifunctional ligand with an attached pyruvate acetal, a ligand for human amyloid P component, and conjugation to poly[acrylamide-co-(3-azidopropylmethacrylamide)] produced a polymer that neutralized Stx2a in a mouse model of Shigatoxemia.


Assuntos
Dissacarídeos/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Toxina Shiga II/química , Animais , Configuração de Carboidratos , Sequência de Carboidratos , Cristalografia por Raios X , Dissacarídeos/metabolismo , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Toxina Shiga II/antagonistas & inibidores , Toxina Shiga II/metabolismo , Análise de Sobrevida , Toxemia/prevenção & controle
2.
Proc Natl Acad Sci U S A ; 105(44): 16837-42, 2008 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-18955695

RESUMO

We demonstrate that interactions between multimeric receptors and multivalent ligands are dramatically enhanced by recruiting a complementary templating receptor such as an endogenous multimeric protein but only when individual ligands are attached to a polymer as preorganized, covalent, heterobifunctional pairs. This effect cannot be replicated by a multivalent ligand if the same recognition elements are independently arrayed on the scaffold. Application of this principle offers an approach to create high-avidity inhibitors for multimeric receptors. Judicious selection of the ligand that engages the templating protein allows appropriate effector function to be incorporated in the polymeric construct, thereby providing an opportunity for therapeutic applications. The power of this approach is exemplified by the design of exceptionally potent Escherichia coli Shiga toxin antagonists that protect transgenic mice that constitutively express a human pentraxin, serum amyloid P component.


Assuntos
Antibacterianos/química , Escherichia coli O157/efeitos dos fármacos , Toxina Shiga I/antagonistas & inibidores , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Escherichia coli O157/metabolismo , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Polímeros/síntese química , Polímeros/química , Polímeros/farmacologia , Componente Amiloide P Sérico/metabolismo , Toxina Shiga I/química
3.
Carbohydr Res ; 378: 4-14, 2013 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-23768952

RESUMO

Hemolytic uremic syndrome is a potentially fatal complication of food poisoning caused by Escherichia coli O157:H7, especially those strains that produce the Stx2 Shiga toxin. Multivalent inhibitors based on the P(k) trisaccharide are most effective against Stx1 the less dangerous of the two Shiga toxins. Inhibitors containing a terminal 2-acetamido-2-deoxy-α-d-galactopyranosyl residue in place of the terminal α-d-galactopyranosyl residue of P(k) trisaccharide have been shown to exhibit preferential binding to Stx2. A multivalent heterobifunctional P(k) analog containing 2-acetamido-2-deoxy-α-d-galactopyranose has been synthesized in a format that facilitates the ablation of toxin activity via supramolecular complex formation between Stx and the endogenous protein, Human serum amyloid P component (HuSAP).


Assuntos
Escherichia coli O157/metabolismo , Galactose/síntese química , Galactose/metabolismo , Toxina Shiga II/metabolismo , Técnicas de Química Sintética , Galactose/química , Humanos , Ligantes , Modelos Moleculares , Oligossacarídeos/química , Ligação Proteica , Conformação Proteica , Toxina Shiga II/biossíntese , Toxina Shiga II/química , Especificidade por Substrato
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