HIMS PhD research leads to Very Important Paper in ChemBioChem

Article on protein mimicry is featured on the cover

5 January 2015

A recent paper by Linde Smeenk in the journal ChemBioChem, summarizing her PhD research at the Van 't Hoff Institute for Molecular Sciences, has been designated as 'Very Important Paper'. The cover graphic of the January issue of ChemBioChem illustrates Smeenk's research, showing how small peptide constructs can mimick specific antibody binding sites ('epitopes') on natural proteins.

Mimicking the binding surface of a protein with peptide-based “small molecules” remains a key challenge in biomedical sciences. In order to achieve maximal binding, different peptide domains involved in binding need to be properly linked and positioned onto a core scaffold molecule.

Novel methodology 

In the ChemBioChem paper Linde Smeenk describes a novel methodology for producing peptide-based mimics of discontinuous epitopes on hFSHβ and hCGβ proteins. Her paper articulates the need for multiple constraints for successful mimicry of these complex epitopes. Only then does the tertiary structure of the peptide-mimics equal that of the natural protein.

Cover ChemBioChem 2015-1

The cover picture shows the X-ray crystal structure of hCGβ (the so-called ‘pregnancy hormone’) in blue, in complex with a monoclonal antibody (mAb3468) in green. The structure illustrates the molecular complexity of the discontinuous and conformational β1/β3 binding site on hCGβ, and further suggests that the binding surfaces of hCGβ and mAb3468 only interact efficiently when the correct secondary and tertiairy structure is adopted.

Smeenk's research demonstrates that tri- and tetracyclic peptide-mimics show an over 100-fold improvement in binding when compared to linear and single-loop peptides lacking the tertiary structure. Her newly developed mimics may eventually provide novel therapeutics or ultimately be used as synthetic vaccines.

Linde Smeenk

Linde Smeenk.

Dick Stufkens prize

Linde Smeenk currently holds a postdoc position with the group of Prof. Helma Wennemers at the Organic Chemistry Laboratory of ETH Zurich. In 2013 she was awarded the Dick Stufkens prize for her research, supervised by Dr Jan van Maarseveen and Prof. Peter Timmerman of the Synthetic Organic Chemistry research group at the Van 't Hoff Institute for Molecular Sciences. Her PhD research was financially supported by the Netherlands Organisation for Scientific Research NWO and performed in close cooperation with PepScan BV and Mologic Ltd. Parts of the work have been patented.

Article

Linde E.J. Smeenk, Drohpatie Timmers-Parohi, Joris J. Benschop, Wouter C. Puijk, Henk Hiemstra, Jan H. van Maarseveen and Peter Timmerman: Reconstructing the Discontinuous and Conformational β1/β3-Loop Binding Site on hFSH/hCG by Using Highly Constrained Multicyclic Peptides ChemBioChem, article first published online : 2 DEC 2014, DOI: 10.1002/cbic.201402540