Events
MoSMed Research Seminar: Prof Norbert Sewald
- Venue: Chemistry Department, Durham University
- Start: Wed, 24 Jun 2026 14:00:54 BST
- End: Wed, 24 Jun 2026 15:00:14 BST
We are delighted to welcome Prof Norbert Sewald from Bielefeld University to Durham University.
Title: Halogenated Natural Products: Enzymatic Halogenation and Application in Tumor Therapy
Abstract: Biocatalysis provides powerful and selective tools for the incorporation of halogen atoms into complex biomolecules, enabling new strategies for the functionalization of peptides and proteins. In particular, halogenated aromatic amino acids such as 5-, 6-, and 7-bromotryptophan serve as versatile handles for late-stage diversification. Enzymatic halogenation offers efficient access to these building blocks, which can be incorporated into peptides by solid-phase synthesis and subsequently modified via transition metal-catalyzed cross-coupling reactions under conditions orthogonal to native peptide functionalities.
Beyond synthetic incorporation, post-translational halogenation of proteins has recently emerged as a highly attractive approach. Engineered variants of tryptophan halogenases, such as Thal mutants, enable the selective bromination of a C-terminal tryptophan within a minimal peptide sequence (BromoTrp tag). This transformation can be achieved in a streamlined coexpression system named Brocoli (Brominating E. coli), allowing bromination in unprotected peptides and proteins in a single cultivation and purification step. Subsequent Pd-catalyzed Suzuki cross-coupling reactions demonstrate the potential of this methodology for bioorthogonal functionalization and conjugation directly on biomacromolecules.
Halogenated natural products themselves represent a rich source of structurally diverse and highly potent bioactive compounds with significant potential in cancer therapy. Among these, cryptophycins, 16-membered macrocyclic depsipeptides originally isolated from cyanobacteria, stand out due to their extraordinary cytotoxicity and their ability to disrupt microtubule dynamics through high-affinity binding to tubulin. Their potency, which exceeds that of established chemotherapeutics such as paclitaxel and vinblastine by several orders of magnitude, makes them promising payloads for targeted drug delivery systems.
A central challenge in the development of cryptophycin-based therapeutics lies in the introduction of functional groups that enable conjugation to targeting moieties without compromising biological activity. Structure-based design, supported by cryo-EM, X-ray crystallography, and QSAR analyses, has identified strategic modification sites, particularly at unit D, allowing the generation of conjugable analogues. These derivatives retain strong tubulin-binding affinity and reveal novel interactions, including binding to a previously unrecognized β-T5-loop site, a critical region involved in microtubule assembly.
Advances in synthetic chemistry have enabled efficient access to structurally modified cryptophycins. These modifications preserve cytotoxic activity while expanding chemical versatility. Furthermore, conjugation strategies have facilitated the attachment of targeting ligands to promote selective uptake into tumor cells.
Together, these developments highlight the synergy between biocatalysis and chemical synthesis in expanding the toolbox of halogenated natural products and derivatives, paving the way for next-generation tumor-targeting therapeutics with enhanced selectivity, modularity, and functional diversity.
