Total Synthesis of the Natural Product Talarolide A Reveals a Unique Structural Conformation in Hydroxamate-Containing Cyclic Peptides

Title: Total Synthesis of the Natural Product Talarolide A Reveals a Unique Structural Conformation in Hydroxamate-Containing Cyclic Peptides

Speaker: Waleed M. Hussein, Centre for Chemistry and Drug Discovery, Institute for Molecular Bioscience, UQ

Abstract: Using a solid-phase synthetic strategy, we report the successful total synthesis of talarolide A, a marine-derived cyclic peptide featuring a rare hydroxamate hydrogen-bond bridge. Strategic disconnection enabled the assembly of a protected linear precursor, followed by sequential deprotection and macrocyclization. We found that cyclizing the fully deprotected peptide was essential to promote correct conformational folding and achieve the natural product’s structure. This approach not only yielded talarolide A but also unveiled a non-canonical atropisomer (atrop-talarolide A), highlighting the underexplored role of hydroxamate-mediated hydrogen bonding in driving atropisomerism in non-ribosomal peptide synthetase (NRPS)-derived peptides.

Biography: Dr. Waleed M. Hussein is a Senior Research Officer at the Institute for Molecular Bioscience (IMB), The University of Queensland. He is an experienced synthetic and medicinal chemist with over 15 years of research expertise in organic synthesis, peptide chemistry, and drug development. Dr. Hussein’s research spans a wide range of therapeutic applications, including the design and synthesis of natural products, small molecules, and peptide-based therapeutics. He has made significant contributions to the development of peptide-based vaccines and immunomodulatory adjuvants, including a patented squalene-based nanoemulsion adjuvant. His work also extends to gene delivery systems, including the development of platforms for siRNA and mRNA delivery. He has held research positions for 12 years in the School of Chemistry and Molecular Biosciences (SCMB) at UQ, one year at Northeastern University in Boston, and the past three years at IMB, where he has been actively involved in collaborative drug discovery projects with QEDDI and UniQuest. Dr. Hussein has authored more than 120 peer-reviewed publications in high-impact journals and holds an h-index of 31. His expertise includes multi-step organic synthesis (from milligram to gram scale), cyclic peptides, SAR-driven analogue design, structural elucidation (NMR, LCMS), molecular modelling, and the development of delivery systems for complex biomolecules. He is passionate about translational research and bridging academic innovation with industry needs. His current work reflects a strong commitment to collaborative science, innovation in therapeutic development, and mentoring the next generation of researchers.