1. Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile.
- Author
-
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, and Marsault É
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Apelin Receptors chemistry, Apelin Receptors metabolism, Blood Pressure drug effects, GTP-Binding Protein alpha Subunits, G12-G13 chemistry, GTP-Binding Protein alpha Subunits, G12-G13 metabolism, Half-Life, Humans, Intercellular Signaling Peptides and Proteins chemistry, Intercellular Signaling Peptides and Proteins pharmacology, Male, Protein Binding, Protein Stability, Rats, Rats, Sprague-Dawley, Intercellular Signaling Peptides and Proteins metabolism, Signal Transduction drug effects
- Abstract
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
i 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbz g; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbz g, Ki 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 ( t1/2 5.8-7.3 h in rat plasma) and in vivo .- Published
- 2021
- Full Text
- View/download PDF