Application O-N Intramolecular Acyl Migration Reaction in the Development of Peptide-based Vaccines — ASN Events

Application O-N Intramolecular Acyl Migration Reaction in the Development of Peptide-based Vaccines (#17)

Mariusz Skwarczynski 1 , Waleed M Hussein 1 , Jariya Kowapradit 1 , Tzu-YU Liu 1 , Zyta M Ziora 1 , Istvan Toth 1 2
  1. School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia 4072, QLD, Australia
  2. School of Pharmacy, University of Queensland, Brisbane, QLD, Australia

The O–N intramolecular acyl migration is a well-known simple rearrangement which proceeds under very mild aqueous conditions. In the last decade, this reaction has been intensively studied and several applications of this rearrangement in medicinal chemistry have appeared. O–N Intramolecular acyl migration has been employed, for example, in prodrug strategies, for the synthesis of peptides containing difficult sequences via “O-acyl isopeptide method”, and in the design of pH-, photo- or enzyme-triggered click peptides [1].

            Recently we have utilized this rearrangement to produce potential peptide-based vaccine against Group A Streptococcal infection and cervical cancer. In our attempts to produce new vaccine delivery system O-acyl isopeptides were conjugated to peptide antigens [2]. The conjugates were converted to “parent” peptides via the pH-triggered O–N acyl migration reaction. The parent peptides aggregated into fibrils with potential immunostimulatory activity [3].  Aggregation of produced peptides induced desired secondary conformation of antigens. It is believed that this approach may serve as a new self-adjuvanting delivery system for peptide-based vaccines. Such vaccines could be stable when stored in a non-aggregative form, and then converted on demand to the active form in pH-controlled manner.

            We have also applied this reaction to produce self-adjuvanting anticancer vaccine. Significant difficulties were faced when Human papillomavirus (HPV)-derived peptide antigens were synthesized using standard SPPS. Therefore, microwave-assisted Fmoc-SPPS was applied in combination with the isopeptide strategy to establish a new method for the rapid synthesis of antigens which include difficult sequence [4]. The model peptide was produced in one day using the method developed, in contrast with two weeks using classical isopeptide strategy. Both methods produced the target peptide in high yield and purity, while classical SPPS did not result in the desired product. The obtained peptide antigens were used to produce highly efficient peptide-polymer-based vaccine against cervical cancer [5].

  1. Skwarczynski, M.; Kiso, Y. Application of the O-N intramolecular acyl migration reaction in medicinal chemistry. Curr. Med. Chem. 2007, 14, 2813-2823.
  2. Skwarczynski, M.; Kowapradit, J.; Ziora, Z. M.; Toth, I. pH-Triggered peptide self-assembly into fibrils: a potential peptide-based subunit vaccine delivery platform. Biochemical Compounds, 2013, 1: 2. doi: 10.7243/2052-9341-1-2.
  3. Skwarczynski, M.; Toth, I. Peptide-Based Subunit Nanovaccines. Current Drug Delivery 2011, 8, 282-289.
  4. Hussein, W.M.; Liu, T.Y.; Toth, I.; Skwarczynski, M. Microwave-Assisted Synthesis of Difficult Sequence-Containing Peptide Using the Isopeptide Method. Org. Biomol. Chem., 2013, 11, 2370–2376.
  5. Liu, T.Y.; Hussein, W.M.; Jia, Z.; Ziora, Z.M.; McMillan, A.J.; Monteiro, M.F.; Toth, I.; Skwarczynski, M. Self-adjuvanting polymer-peptide conjugates as therapeutic vaccine candidates against cervical cancer. Biomacromolecules, 2013, 14, 2798-2806.