Oral Presentation The 16th Australian Peptide Conference 2025

Total synthesis of the antifungal and antiviral cyclic lipodepsipeptides verlamelins A and B (128391)

Urawadee Rajchakit 1 2 , Dennise Palpal-latoc 1 2 3 , Crystal Lin 1 , Bernhard Hauk 4 , Sung Hyun Yang 1 2 , Louise A. Stubbing 1 , Freda F. Li 1 , Alan J. Cameron 1 2 3 , Margaret A. Brimble 1 2 3
  1. School of Chemical Sciences, The University of Auckland, Auckland Central, Auckland, New Zealand
  2. School of Biological Sciences, The University of Auckland, Auckland Central, Auckland, New Zealand
  3. Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland Central, Auckland, New Zealand
  4. Department of Chemistry, Johannes Gutenberg University of Mainz, Mainz, Rhineland Palatinate, Germany

The prevalence of fungal infections as well as the significant increase of antifungal resistance pose a pivotal threat to both public health and food safety worldwide.1 Resistance development is especially problematic due to the structural similarity of agricultural fungicides and clinical antifungal agents, such as those belonging to the triazole class. This overlap raises pressing concerns of the pathogens developing cross-resistance.1 Considering this challenge, there is an urgent need for new antifungal medicines with distinctive modes of action for both clinical and agricultural applications. Although antifungal therapy has been dominated by synthetic drugs, natural products continue to offer a promising platform for discovering new bioactive compounds. Among these, cyclic lipopeptides have shown considerable potential due to their broad-spectrum activity. The cyclic lipodepsipeptides, verlamelins A and B, exhibit potent antifungal activity towards several phytopathogenic fungi (e.g. Cochliobolus miyabeanus and Alternalia solani) but are inactive towards human pathogenic fungi (e.g. Candida albicans), making them attractive candidates for the development of agricultural antifungals. Interestingly, they also demonstrate antiviral properties towards herpes simplex virus (HSV-1) and accordingly hold the potential as an effective therapeutic class in clinical settings. Herein, we report the first total synthesis of verlamelins A and B. After preparing the key silyl protected (S)-5-hydroxytetradecanoic acid lipid building block and trialling three disconnection strategies, verlamelins A and B were afforded using an efficient combination of solid-phase peptide synthesis (SPPS) to form the linear depsipeptides, followed by late-stage solution-phase macrolactamization. This synthesis approach offers a platform for the preparation of analogues for structure-activity relationship (SAR) studies, which could provide clarification towards their mechanism of action and generate synthetic derivatives with superior activity or reduced synthetic complexity.

  1. Fisher, M. C., Alastruey-Izquierdo, A., Berman, J., Bicanic, T., Bignell, E. M., Bowyer, P., ... & Verweij, P. E. (2022). Tackling the emerging threat of antifungal resistance to human health. Nat. Rev. Microbiol., 20(9), 557-571.