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.

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