74825-83-5Relevant 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.
Structure-Activity Relationships of Small Phosphopeptides, Inhibitors of Grb2 SH2 Domain, and Their Prodrugs
Liu, Wang-Qing,Vidal, Michel,Olszowy, Catherine,Million, Emmanuelle,Lenoir, Christine,Dh?tel, Hélène,Garbay, Christiane
, p. 1223 - 1233 (2007/10/03)
To develop potential antitumor agents directed toward HER2/ErbB2 overexpression in cancer, we have designed inhibitors of the recognition between the phosphotyrosine of the receptor and the SH2 domain of the adaptor protein Grb2. In the first part of the paper, we report the synthesis of mimetics of the constrained (α-Me)phosphotyrosine residue such as (α-Me)-4-phosphonomethylphenylalanine (-CH2PO3H 2), (α-Me) 4-phosphonodifluoromethylphenylalanine (-CF 2PO3H2), and (α -Me)-4-phosphonophenylalanine (-PO3H2). The incorporation of these residues in the mAZ-pTyr-Xaa-Asn-NH2 series provided compounds with very high affinity for the Grb2 SH2 domain, in the 10 -8-10-9 range of Kd values. These compounds behave as potent antagonists of the Grb2-Shc interaction. Our results highlight the importance of the doubly negative charge borne by the pY + 1 amino acid in accordance with the interactions observed in the complex crystallized between mAZ-pTyr-(αMe)pTyr-Asn-NH2 and the Grb2 SH2 domain. mAZ-pTyr-(αMe)pTyr-Asn-NH2 was derivatized as the S-acetyl thioester (SATE) of the phosphotyrosine residues, and its surrogates provided prodrugs with very potent antiproliferative activity on cells overexpressing HER2/ErbB2, with ED50 values amounting to 0.1 μM. Finally a new prodrug is put forth under the form of a monobenzyl ester of phosphate group that is as active as and much easier to synthesize than SATE prodrugs. These compounds show promising activity for further testing on in vivo models.
Novel Analogues of Enkephalin: Identification of Functional Groups Required for Biological Activity
Gorin, Fredric A.,Balasubramanian, T. M.,Cicero, Theodore J.,Schwietzer, John,Marshall, Garland R.
, p. 1113 - 1122 (2007/10/02)
Novel tri- and tetrapeptide analogues of enkephalin, in conjunction with earlier structure-activity data, confirm that chemical substituents present in the first and fourth residues of enkephalin are required for in vitro biological activity.A class of ar
