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New chemical reagents for protein modification create interesting opportunities in drug discovery

Researchers from Prof. Thomas Poulsen’s research group, in collaboration with scientists at the Research Unit for Molecular Medicine (MMF) at Aarhus University Hospital, have published two articles on two new reagent classes that each break new ground for covalent protein modification in drug design.

Graphic of the chemical bond related to the publication in Angewandte Chemie.
Graphic of the chemical bond related to the publication in Angewandte Chemie.

Reagents for direct chemical functionalisation of proteins form the basis for preparation of advanced biopharmaceuticals – such as antibody-drug conjugates (ADCs) – as well as precision medicines that work via covalent chemical bonding of the drug to the target protein. Therefore, the introduction of new reagent classes, which is what Prof. Thomas Poulsen and colleagues have done, expands the options for designing new drugs.

The first study is published in Bioconjugate Chemistry and shows that so-called oxSTEF-reagents, which enable highly efficient targeting of surface-exposed disulfide bonds, can selectively modify a suite of different proteins, including human growth hormone.  In more colloquial language, that means the researchers have found a way to ‘hijack’ a type of weak bond – which are found in almost all proteins – to e.g. selectively modify protein hormones, enzymes or antibodies. Moreover, the researchers show how they can generate proteins with highly uniform modification patterns, which can otherwise be a significant challenge.

In the second study, published in Angewandte Chemie, the research team pioneer the first use of alpha-lactams as covalent molecular tools for chemical biology. The alpha-lactam group is intrinsically unstable due to its significant strain and has so far been regarded as a curiosity. Basically, it has never before been possible to use this class of very exotic molecules for any type of chemical-biological experiments, but this barrier has now been overcome, which creates exciting possibilities within drug design.

Actually, both studies provide completely new avenues for covalent ligand design – a major area within contemporary drug discovery – which can hopefully aid the development of new drugs with better impact and less side effects.

Supplemental information

   Type of studies/methods        Experimental studies
   External collaborators       Article in Bioconjugate Chemistry: Novo Nordisk A/S

   Article in Angewandte Chemie: None
   External funding    Article in Bioconjugate Chemistry:
   This project received funding from the Novo Nordisk
   Foundation. Grant Number: NNF19OC0054782
   Article Angewandte Chemie:
   This project received funding from the European
   Research Council under the European Union’s
   Horizon 2020 research and innovation programme
   (grant agreement no. 865738) to Thomas B. Poulsen 
   and from the Novo Nordisk Foundation. Grant
   Number: NNF19OC0054782.
   Conflicts of interest    None      
   Other        N/A      
   Links to scientific articles          Article in Bioconjugate Chemistry:

   Article in Angewandte Chemie: 
   Contact information     PROF. Thomas B. Poulsen
   Department of Chemistry, AARHUS UNIVERSITY
   Telephone: +45 61 14 18 44.
   EMAIL: thpou@chem.au.dk