Titre : Synthesis of β-substituted-α-amino γ-lactams to study the influence of peptide-based conformational constraint on IL-1 allosteric modulators
Endroit : Pavillon J.-Armand Bombardier, salle 1035 à 11 h 00.
Cette conférence sera prononcée par Madame Azade Geranurimi, étudiante au doctorat, du laboratoire de William Lubell, professeur au Département de chimie de l'Université de Montréal.
Résumé:
Peptide 101.10 (rytvela) is an allosteric modulator of the interleukin 1 receptor, which has potential clinical applications in inflammation. The threonine residue of this peptide may play an important role in activity and receptor recognition through hydrogen bonding by way of the side chain hydroxy group. Towards the design of constrained threonine analogs to explore the impact of conformation on peptide biology, we have targeted the synthesis of α-amino-β-hydroxy-γ-lactam (Hgl) analogs of 101.10 (rytvela). By restricting rotation about the ω, ψ, and χ dihedral angles, the Hgl residue is expected to stabilize a potential β-turn structure that may be responsible for potency and selectivity. Eight different isomers of the Hgl-Val dipeptide were synthesized for insertion into the sequence of 101.10 (rytvela) by solid phase synthesis to investigate the influence of configuration on conformation and biological activity. In addition, four isomers of α-amino-γ-lactam (Agl)-Val dipeptides have been synthesized and incorporated into the sequence of 101.10 (rytvela) as controls to explore the effect of hydroxyl group in biological activity. All of Agl and Hgl diasteriomers of 101.10 have been biologically tested. Preliminary biological studies were promising and resulted in further investigation to understand the nature of hydroxyl group interaction with the receptor and possible effects on conformation by functionalizing it to series of groups such as SH, NH2, F, CO2H, CONH2 and triazole. So far thiol and amine substituted α-amino-γ-lactam have been synthesized and the rest are in perspective.
