181824-45-3Relevant academic research and scientific papers
Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile
Tran, Kien,Van Den Hauwe, Robin,Sainsily, Xavier,Couvineau, Pierre,C?té, Jér?me,Simard, Louise,Echevarria, Marco,Murza, Alexandre,Serre, Alexandra,Théroux, Léa,Saibi, Sabrina,Haroune, Lounès,Longpré, Jean-Michel,Lesur, Olivier,Auger-Messier, Mannix,Spino, Claude,Bouvier, Michel,Sarret, Philippe,Ballet, Steven,Marsault, éric
supporting information, p. 5345 - 5364 (2021/02/16)
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 (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; 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-Dbzg, 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.
Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors
Maillard, Michel C.,Brookfield, Frederick A.,Courtney, Stephen M.,Eustache, Florence M.,Gemkow, Mark J.,Handel, Rebecca K.,Johnson, Laura C.,Johnson, Peter D.,Kerry, Mark A.,Krieger, Florian,Meniconi, Mirco,Mu?oz-Sanjuán, Ignacio,Palfrey, Jordan J.,Park, Hyunsun,Schaertl, Sabine,Taylor, Malcolm G.,Weddell, Derek,Dominguez, Celia
experimental part, p. 5833 - 5851 (2011/10/31)
Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and ～200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.
