Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 3 de 3
Filter
Add more filters










Database
Language
Publication year range
1.
Nat Chem Biol ; 15(7): 699-709, 2019 07.
Article in English | MEDLINE | ID: mdl-31061498

ABSTRACT

Chondroitin sulfate (CS) and heparan sulfate (HS) are glycosaminoglycans that both bind the receptor-type protein tyrosine phosphatase PTPRσ, affecting axonal regeneration. CS inhibits axonal growth, while HS promotes it. Here, we have prepared a library of HS octasaccharides and, together with synthetic CS oligomers, we found that PTPRσ preferentially interacts with CS-E-a rare sulfation pattern in natural CS-and most HS oligomers bearing sulfate and sulfamate groups. Consequently, short and long stretches of natural CS and HS, respectively, bind to PTPRσ. CS activates PTPRσ, which dephosphorylates cortactin-herein identified as a new PTPRσ substrate-and disrupts autophagy flux at the autophagosome-lysosome fusion step. Such disruption is required and sufficient for dystrophic endball formation and inhibition of axonal regeneration. Therefore, sulfation patterns determine the length of the glycosaminoglycan segment that bind to PTPRσ and define the fate of axonal regeneration through a mechanism involving PTPRσ, cortactin and autophagy.


Subject(s)
Autophagy/drug effects , Chondroitin Sulfates/pharmacology , Cortactin/metabolism , Heparitin Sulfate/pharmacology , Nerve Regeneration/drug effects , Receptor-Like Protein Tyrosine Phosphatases, Class 5/metabolism , Animals , Chondroitin Sulfates/chemistry , Heparitin Sulfate/chemistry , Humans , Mice
2.
Arterioscler Thromb Vasc Biol ; 39(4): 694-703, 2019 04.
Article in English | MEDLINE | ID: mdl-30727756

ABSTRACT

Objective- PAR4 (protease-activated receptor 4), one of the thrombin receptors in human platelets, has emerged as a promising target for the treatment of arterial thrombotic disease. Previous studies implied that thrombin exosite II, known as a binding site for heparin, may be involved in thrombin-induced PAR4 activation. In the present study, a heparin octasaccharide analog containing the thrombin exosite II-binding domain of heparin was chemically synthesized and investigated for anti-PAR4 effect. Approach and Results- PAR4-mediated platelet aggregation was examined using either thrombin in the presence of a PAR1 antagonist or γ-thrombin, which selectively activates PAR4. SCH-28 specifically inhibits PAR4-mediated platelet aggregation, as well as the signaling events downstream of PAR4 in response to thrombin. Moreover, SCH-28 prevents thrombin-induced ß-arrestin recruitment to PAR4 but not PAR1 in Chinese Hamster Ovary-K1 cells using a commercial enzymatic complementation assay. Compared with heparin, SCH-28 is more potent in inhibiting PAR4-mediated platelet aggregation but has no significant anticoagulant activity. In an in vitro thrombosis model, SCH-28 reduces thrombus formation under whole blood arterial flow conditions. Conclusions- SCH-28, a synthetic small-molecular and nonanticoagulant heparin analog, inhibits thrombin-induced PAR4 activation by interfering with thrombin exosite II, a mechanism of action distinct from other PAR4 inhibitors that target the receptor. The characteristics of SCH-28 provide a new strategy for targeting PAR4 with the potential for the treatment of arterial thrombosis.


Subject(s)
Antithrombins/pharmacology , Heparin/chemistry , Oligosaccharides/pharmacology , Platelet Aggregation/drug effects , Receptors, Thrombin/antagonists & inhibitors , Animals , Antithrombins/chemical synthesis , CHO Cells , Calcium Signaling/drug effects , Computer Simulation , Cricetulus , Drug Evaluation, Preclinical , Humans , In Vitro Techniques , Models, Molecular , Recombinant Proteins/drug effects , Thrombin/pharmacology , Thrombosis/prevention & control
3.
J Am Chem Soc ; 136(41): 14425-31, 2014 Oct 15.
Article in English | MEDLINE | ID: mdl-25291402

ABSTRACT

Living organisms employ glycans as recognition elements because of their large structural information density. Well-defined sugar structures are needed to fully understand and take advantage of glycan functions, but sufficient quantities of these compounds cannot be readily obtained from natural sources and have to be synthesized. Among the bottlenecks in the chemical synthesis of complex glycans is the preparation of suitably protected monosaccharide building blocks. Thus, easy, rapid, and efficient methods for building-block acquisition are desirable. Herein, we describe routes directly starting from the free sugars toward notable monosaccharide derivatives through microwave-assisted one-pot synthesis. The procedure followed the in situ generation of per-O-trimethylsilylated monosaccharide intermediates, which provided 1,6-anhydrosugars or thioglycosides upon treatment with either trimethylsilyl trifluoromethanesulfonate or trimethyl(4-methylphenylthio)silane and ZnI2, respectively, under microwave irradiation. We successfully extended the methodology to regioselective protecting group installation and manipulation toward a number of thioglucosides and the glycosylation of persilylated derivatives, all of which were conducted in a single vessel. These developed approaches open the possibility for generating arrays of suitably protected building blocks for oligosaccharide assembly in a short period with minimal number of purification stages.


Subject(s)
Microwaves , Oligosaccharides/chemical synthesis , Thioglycosides/chemical synthesis , Carbohydrate Conformation , Oligosaccharides/chemistry , Thioglycosides/chemistry
SELECTION OF CITATIONS
SEARCH DETAIL
...