Development of transition state analogues targeting chitinases and oligosaccharyl transferase

Oligosaccharyl transferase (OT) plays a central role in the biosynthesis of asparagine-linked glycoproteins in eukaryotic systems. The glycosylation step catalyzed by OT involves the co-translational transfer of a tetradecasaccharide from a dolichyl-pyrophosphate carrier to an asparagine side-chain within the Asn-Xaa-Ser/Thr sequence of a nascent polypeptide. Chitinases, which was emerged as a therapeutic target in combating asthma, are [beta]-1,4-N-acetylglucosaminidases that hydrolyze chitin to generate the disaccharide chitobiose Although the reactions catalyzed by the two enzymes follow different pathways, they are believed to share similar transition states involving an oxocarbenium ion. To understand the mechanism of OT and discover potent and selective inhibitors against different chitinases, our intent was to utilize the common transition state analogue for both enzymes and systematically introduce additional binding determinants. The pseudo-disaccharides containing an imino sugar were designed to target the oxocarbenium ion like transition state. The pseudo-disaccharides containing imino sugar were synthesized and evaluated at inhibitors for OT and chitinases.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Chemistry.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2006

Author dc:creator

• Choi, Seungjib

Advisor dc:contributor.advisor

• Barbara Imperiali.

• Chemistry.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/37694

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/37694