Poster Presentation 14th Australian Peptide Conference 2022

Novel melanocortin receptor ligands and conjugates produced by nucleophilic aromatic substitution (#249)

Wenxiao K Yue 1 , Tianxia Zhang 1 , Rekha Shandre Mugan 1 , Philip E Thompson 1 , Colin W Pouton 1
  1. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

The melanocortin receptors (MCRs) represent a class of important targets in the development of novel therapeutics and have been a benchmark exemplar for cyclic peptidomimetic drugs with several peptidic ligands approved for therapeutic use in recent years.1 We have been interested in pursuing melanocortin ligands via novel chemistry to create new chemical matter and strategies that can have broad applicability in peptidomimetic-based drug design. Nucleophilic aromatic substitution (SNAr) is an effective cyclisation method that is orthogonal to conventional peptide chemistries. Application of this strategy for preparing alkyl-aryl ether or biaryl ether bridged peptide macrocycles is well documented, but focus has been primarily on nitro-activated SNArs.2 The synthetic applicability of SNAr macrocyclisation involving other substituents has been neglected.

With the aim to further broaden the scope and utility of SNAr macrocyclisation, we established a range of melanocortin receptor-targeting peptides bearing nitro-, cyano- and ethynyl-fluoroarenes as substrates for SNAr mediated macrocyclisations with cysteine residues. The resultant alkylthioaryl-bridged macrocycles were subjected to further structural modification, providing new points for additional conjugate preparation. The effects of those modifications were evaluated for their biological activities at MCRs. Libraries of 19- to 22-membered heterodectic macrocyclic peptides were prepared. The synthetic make-up of the cyclic peptides and post-cyclisation functionalisation resulted in a diverse series of MCR agonists with sub-nanomolar EC50 levels at MC1R and MC4R, and different receptor subtype selectivity with respect to MC3R and MC5R. The ability to conjugate prosthetic groups has allowed attachment of various elements such as fluorophores, radiotracers and moieties that can modify pharmaceutical properties.

The successful extension of the domain of SNAr reactivity to substrates containing cyano and ethynyl groups and the feasibility of creating functionalised macrocyclic scaffolds boost the utility of SNAr in macrocyclic peptidomimetic design, expediting access to diversity-oriented ligand libraries with enhanced properties.

  1. Ericson, M. D.; Lensing, C. J.; Fleming, K. A.; Schlasner, K. N.; Doering, S. R.; Haskell-Luevano, C. Biochim. Biophys. Acta, Mol. Basis Dis. 2017, 1863, 2414-2435.
  2. (a) Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961-2004. (b) Peterson, M. L. The synthesis of macrocycles for drug discovery. In Macrocycles in drug discovery; Levin, J.; Eds.; The Royal Society of Chemistry: Cambridge, 2015; pp 398-486.