University of Montreal
Conception of Prostaglandin F2α Receptor Allosteric Modulators that Delay Preterm Birth by Harnessing the Paired Utility of Aza-Amino Acyl Proline and Indolizidinone Amino Acid Residues for Peptide Mimicry
Aza-amino acyl prolines and indolizidinone amino acids share common conformational preferences as demonstrated in second mitochondria-derived activator of caspase protein peptidomimetics, in calcitonin gene-related peptide antagonists, and in modulators of the prostaglandin-F2α receptor, FP.
Systematic study of the conformation and side chain functions of the central turn dipeptide residue of FP modulators has been used to demonstrate the sensitive relationships between activity and topology. Moreover, study of aza-Gly-Pro and aza-Phe-Pro analogs in a murine preterm labor model featuring treatment with lipopolysaccharide demonstrated their capacity to extend significantly, >20 h, the average time of delivery offering new prototypes for delaying premature birth.
Our presentation will highlight the relevance of having two classes of scaffolds to mimic the same conformation and their use to facilitate lead development of FP modulators.