1. N-terminal guanidinylation of TIPP (Tyr-Tic-Phe-Phe) peptides results in major changes of the opioid activity profile
Grazyna Weltrowska, Thi M-D Nguyen, Nga N Chung, Brian C Wilkes, Peter W Schiller Bioorg Med Chem Lett. 2013 Sep 15;23(18):5082-5. doi: 10.1016/j.bmcl.2013.07.036. Epub 2013 Jul 23.
Derivatives of peptides of the TIPP (Tyr-Tic-Phe-Phe; Tic=1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) family containing a guanidino (Guan) function in place of the N-terminal amino group were synthesized in an effort to improve their blood-brain barrier permeability. Unexpectedly, N-terminal amidination significantly altered the in vitro opioid activity profiles. Guan-analogues of TIPP-related δ opioid antagonists showed δ partial agonist or mixed δ partial agonist/μ partial agonist activity. Guanidinylation of the mixed μ agonist/δ antagonists H-Dmt-Tic-Phe-Phe-NH2 (DIPP-NH2) and H-Dmt-TicΨ[CH2NH]Phe-Phe-NH2 (DIPP-NH2[Ψ]) converted them to mixed μ agonist/δ agonists. A docking study revealed distinct positioning of DIPP-NH2 and Guan-DIPP-NH2 in the δ receptor binding site. Lys(3)-analogues of DIPP-NH2 and DIPP-NH2[Ψ] (guanidinylated or non-guanidinylated) turned out to be mixed μ/κ agonists with δ antagonist-, δ partial agonist- or δ full agonist activity. Compounds with some of the observed mixed opioid activity profiles have therapeutic potential as analgesics with reduced side effects or for treatment of cocaine addiction.
2. Novel sst(4)-selective somatostatin (SRIF) agonists. 1. Lead identification using a betide scan
Jean Rivier, Judit Erchegyi, Carl Hoeger, Charleen Miller, William Low, Sandra Wenger, Beatrice Waser, Jean-Claude Schaer, Jean Claude Reubi J Med Chem. 2003 Dec 18;46(26):5579-86. doi: 10.1021/jm030243c.
Hypothesizing that structural constraints in somatostatin (SRIF) analogues may result in receptor selectivity, and aiming to characterize the bioactive conformation of somatostatin at each of its five receptors, we carried out an N(beta)-methylated aminoglycine (Agl) scan of the octapeptide H-c[Cys(3)-Phe(6)-Phe(7)-dTrp(8)-Lys(9)-Thr(10)-Phe(11)-Cys(14)]-OH (SRIF numbering) (ODT-8) that is potent at all SRIF receptor subtypes (sst's) but sst(1). We found that H-c[Cys-LAgl(N(beta)Me,benzoyl)-Phe-DTrp-Lys-Thr-Phe-Cys]-OH (4), H-c[Cys-Phe-LAgl(N(beta)Me,benzoyl)-Trp-Lys-Thr-Phe-Cys]-OH (6), H-c[Cys-Phe-LAgl(N(beta)Me,benzoyl)-dTrp-Lys-Thr-Phe-Cys]-OH (8), and H-c[DCys-Phe-LAgl(N(beta)Me,benzoyl)-DTrp-Lys-Thr-Phe-Cys]-OH (10) had high affinity (IC(50) = 14.3, 5.4, 5.2, and 3.4 nM, respectively) and selectivity for sst(4) (>50-fold over the other receptors). The l-configuration at positions 7 and 8 (l(7), l(8)) yields greater sst(4) selectivity than the l(7), d(8) configuration (6 versus 8). Peptides with the d(7), l(8) (7) and d(7), d(8) (9) configurations are significantly less potent at all receptors. H-c[Cys-Phe-Phe-DTrp-LAgl(betaAla)-Thr-Phe-Cys]-OH (16), H-c[Cys-Phe-Phe-DTrp-DAgl(betaAla)-Thr-Phe-Cys]-OH (17), and their N(beta)Me derivatives at position 9 (18, 19) were essentially inactive. Potent but less sst(4)-selective were members of the Agl-scan at positions 10, H-c[Cys-Phe-Phe-dTrp-Lys-lAgl(N(beta)Me,HO-Ac)-Phe-Cys]-OH (20, IC(50) = 6.5 nM), and 11, H-c[Cys-Phe-Phe-DTrp-Lys-Thr-LAgl(N(beta)Me,benzoyl)-Cys]-OH (22, IC(50) = 6.9 nM), while the d-configuration at positions 10 (21) and 11 (23) led to reduced affinity. One of our best analogues, 8, is an agonist when tested for its ability to inhibit forskolin-stimulated cAMP accumulation in sst(4)-transfected CCL39 cells (EC(50) = 1.01 nM). All Agl-containing analogues were first synthesized using unresolved Fmoc-Agl(N(beta)Me,Boc)-OH, and the diastereomers were separated using HPLC. Chiral assignment at the Agl-containing residue was subsequently done using enzymatic degradation and by de novo synthesis in the cases of H-c[Cys-Phe-DAgl(N(beta)Me,benzoyl)-DTrp-Lys-Thr-Phe-Cys]-OH (9) and H-c[DCys-Phe-DAgl(N(beta)Me,benzoyl)-DTrp-Lys-Thr-Phe-Cys]-OH (11), starting with the papain-resolved Fmoc-DAgl(Boc). These results suggested that the orientation of side chains at position 6, 7, or 11 with respect to the side chains of residues 8 and 9 may be independently responsible for sst(4) selectivity.
3. New archetypes in self-assembled Phe-Phe motif induced nanostructures from nucleoside conjugated-diphenylalanines
Dhrubajyoti Datta, Omshanker Tiwari, Krishna N Ganesh Nanoscale. 2018 Feb 15;10(7):3212-3224. doi: 10.1039/c7nr08436f.
During the last two decades, the molecular self-assembly of the short peptide diphenylalanine (Phe-Phe) motif has attracted increasing focus due to its unique morphological structure and utility for potential applications in biomaterial chemistry, sensors and bioelectronics. Due to the ease of their synthetic modifications and a plethora of available experimental tools, the self-assembly of free and protected diphenylalanine scaffolds (H-Phe-Phe-OH, Boc-Phe-Phe-OH and Boc-Phe-Phe-OMe) has unfurled interesting tubular, vesicular or fibrillar morphologies. Developing on this theme, here we attempt to examine the effect of structure and properties (hydrophobic and H-bonding) modifying the functional C-terminus conjugated substituents on Boc-Phe-Phe on its self-assembly process. The consequent self-sorting due to H-bonding, van der Waals force and π-π interactions, generates monodisperse nano-vesicles from these peptides characterized via their SEM, HRTEM, AFM pictures and DLS experiments. The stability of these vesicles to different external stimuli such as pH and temperature, encapsulation of fluorescent probes inside the vesicles and their release by external trigger are reported. The results point to a new direction in the study and applications of the Phe-Phe motif to rationally engineer new functional nano-architectures.
