Combinatorial discovery and automated parallel synthesis of catalytic peptide dendrimers

ORGN 58

Anthony Clouet1, Nhat Quang Nguyen-Trung2, Estelle Delort1, and Jean-Louis Reymond, reymond@ioc.unibe.ch1. (1) Department of Chemistry and Biochemistry, University of Berne, Freiestrasse 3, Berne, 3012, Switzerland, (2) Chemspeed Ltd, Rheinstrasse 32, Augst, 4302, Switzerland
Recently we started to study peptide dendrimers as synthetic models for proteins. Dendrimers are ramified, tree-like molecules. Introducing amino acids within the branches and extremities of dendrimers results in protein-like globular structures without any requirement for folding. We have developed a combinatorial protocol for the preparation of >60'000 member dendrimer libraries by split-and-mix and direct screening for catalytic activity on beads. A library of histidine-containing peptide dendrimers was screened for catalytic hydrolysis of esters, leading to the identification of several catalytic sequences using a fluorogenic ester substrate, as illustrated by the HTS-picture below. A parallel synthesis method was then implemented using the Chemspeed PSW1100 peptide synthesizer for a series of 32 different sequences. Structure-activity relationships in this series revealed mechanistic details about the activity and selectivity of esterolytic peptide dendrimers.

 

Combinatorial, Parallel, and Solid-Phase Chemistry
1:00 PM-4:20 PM, Sunday, 13 March 2005 Convention Center -- Room 10, Oral

Division of Organic Chemistry

The 229th ACS National Meeting, in San Diego, CA, March 13-17, 2005