Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile.

Publication — IRIC

Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (K

0.08-0.18 nM vs Ape13 K

0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Db_zg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, K

0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Db_zg, K

0.08 nM) are the most potent Ape13 analogues activating the Gα₁₂ pathways (53, EC₅₀ Gα₁₂ 2.8 nM vs Ape13, EC₅₀ 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t_1/2 5.8-7.3 h in rat plasma) and in vivo.

Publication date: mai 13, 2021
Principal Investigators: Trân K, Van Den Hauwe R, Sainsily X, Couvineau P, Côté J, Simard L, Echevarria M, Murza A, Serre A, Théroux L, Saibi S, Haroune L, Longpré JM, Lesur O, Auger-Messier M, Spino C, Bouvier M, Sarret P, Ballet S, Marsault E
PubMed reference: J Med Chem 2021;64(9):5345-5364
PubMed ID: 33524256
Affiliation: Département de Pharmacologie-Physiologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.