PubMed Health⌕ Search

Biomedical subjects

Murray Goodman

Publications and source records attributed to Murray Goodman.

30 records · Page 2Linked to original sources
PubMed2003

Incorporation of thioether building blocks into an alphavbeta3-specific RGD peptide: synthesis and biological activity.

We report the design, synthesis, and binding affinities of a family of thioether analogues of the alpha(v)beta(3)-specific compound c[(Mpa)RGDD(tBuG)C]-NH(2). The synthesis of the thioether building blocks is scalable and produced the desired products in good yields. The linear peptides were synthesized on solid supports, followed by cyclization in solution. Our analogues demonstrate interesting binding data to the isolated receptors. In particular, the peptide c[NH-Arg-Gly-Asp-Asp-(tBuG)-Cys(S-CH(2)-CO)]NH(2) (1) exhibits differences in binding when compared to the parent compound and demonstrates potent affinity to the alpha(v)beta(3) and alpha(5)beta(1) receptors while having reduced binding to the alpha(IIb)beta(3) receptor. This result combined with the replacement of the disulfide with a thioether makes this compound interesting for further development.

Amino Acid Sequence↗
PubMed2003

The bold legacy of Emil Fischer.

A century has passed since Emil Fischer won the Nobel Prize in chemistry. From his first synthesis of glycyl-glycine in 1901 he has been a luminary to peptide chemists over the past 100 years. In this paper, a brief summary of some of the major accomplishments in peptide chemistry will be covered followed by a description of several of our own endeavours in peptide chemistry which arose from the discoveries of the giants of our field. We will include the development of a novel activating agent (DEPBT), the synthesis of a novel building block, alpha-methyl-D-cysteine, its incorporation into biologically active opioids, and conclude with the synthesis of dendritic collagen mimetics.

Collagen↗
PubMed2003

Systemic and spinal analgesic activity of a delta-opioid-selective lanthionine enkephalin analog.

A lanthionine enkephalin derivative, Tyr-c[D-Val(L)-Gly-Phe-D-Ala(L)]-OH (DV(L)(2)DA(L)(5)LanEnk), where Val(L) and Ala(L) denote the lanthionine amino acid ends linked via a monosulfide bridge to form the lanthionine structure, was synthesized. It was found to possess selectivity for and potency at the delta versus mu opioid receptor as defined by binding studies and by its respective activity on the mouse vas deferens compared with the guinea pig ileum. The agent produced a potent analgesia after intrathecal and intraperitoneal delivery with ED(50) values being, respectively, 0.19 mucrog and 0.49 mg/kg. The effects of the agent were reversed by the delta-selective antagonist naltrindole. These analgesic actions occurred at doses that had no effect upon general behavior or motor function. These results suggest a potent delta-preferring agent suitable for development as a systemic delta opioid analgesic.

Alanine↗
PubMed2002

Collagen mimetic dendrimers.

The synthesis of single-chain, scaffold (TRIS)- and dendrimer-assembled collagen mimetics (both Gly-Pro-Nleu and Gly-Nleu-Pro sequences) is reported. From the CD spectra and the thermal denaturation studies it can be readily seen that mimetics prepared from the Gly-Nleu-Pro sequence form more thermally stable triple helices than the Gly-Pro-Nleu sequence. Furthermore, the 162-residue collagen mimetic dendrimers exhibit enhanced triple helical stability compared to equivalent scaffold-terminated structures by a substantial increase in the melting temperature in H2O and 2:1 EG/H2O. The concentration dependence for the melting transition was measured which determined that the stabilization effect arises from the intramolecular clustering of the triple helical arrays about the core structure. This ensemble excludes solvent from the interior portion of the array which stabilizes the triple helical bundle.

Biomimetic Materials↗
PubMed2002

Solid-phase synthesis of amine-bridged cyclic enkephalin analogues via on-resin cyclization utilizing the Fukuyama-Mitsunobu reaction.

An efficient solid-phase synthetic route is described for the preparation of 13-membered amine-bridged cyclic enkephalin analogues (ABEs) 1a and 1c-1j (Figure 1) resulting from a sulfonamide-containing peptide whose backbone is bound to a resin. The Fukuyama-Mitsunobu reaction of the 2-nitrobenzenesulfonyl-protected amine bound to the solid support with protected aminoethanol in the presence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD) is utilized to prepare a resin-bound sulfonamide-protected secondary amine. After peptide cyclization, this protected amine functionality becomes the "amine bridge" of the target molecule. In addition, the reagent DIAD was found to be a superior reagent compared to diethyl azodicarboxylate (DEAD) in the solid-phase Fukuyama-Mitsunobu reaction.

Amines↗
PubMed2002

TREN (Tris(2-aminoethyl)amine): an effective scaffold for the assembly of triple helical collagen mimetic structures.

A new scaffold, TREN-(suc-OH)(3) where TREN is tris(2-aminoethyl)amine and suc is the succinic acid spacers, was incorporated to assemble triple helices composed of Gly-Nleu-Pro sequences (Nleu denotes N-isobutylglycine). Extensive biophysical studies which include denaturation studies, CD and NMR spectroscopy, and molecular modeling demonstrated that TREN-[suc-(Gly-Nleu-Pro)(n)-NH(2)](3) (n = 5 and 6) form stable triple helical structures in solution. A comparative analysis of TREN-assembled and KTA-assembled collagen mimetics (KTA denotes Kemp triacid, 1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid) indicates that the flexibility of the TREN scaffold is superior to the KTA scaffold in inducing triple helicity. This effect most likely arises from the flexibility of the TREN scaffold which allows the three peptide chains to adjust their register for a tighter triple helical packing.

Circular Dichroism↗
PubMed2002

Synthesis and biological activities of cyclic lanthionine enkephalin analogues: delta-opioid receptor selective ligands.

The synthesis and biological test results of a series of enkephalin analogues incorporating the lanthionine modification are presented. The syntheses of four monosulfide-bridged analogues of enkephalins, Tyr-c[D-Ala(L)-Gly-Phe-D-Ala(L)]-OH (1a), Tyr-c[D-Val(L)-Gly-Phe-D-Ala(L)]-OH (1b), Tyr-c[D-Ala(L)-Gly-Phe-Ala(L)]-OH (1c), and Tyr-c[D-Val(L)-Gly-Phe-Ala(L)]-OH (1d), where Ala(L) and Val(L) denote the lanthionine amino acid ends linked by a monosulfide bridge to form the lanthionine structure, were successfully carried out via preparation of the linear peptide on solid support and cyclization in solution. In vitro binding assays against mu-, delta-, and kappa-opioid receptors and in vitro tests using GPI and MVD assays revealed that the dimethyl lanthionine analogues 1b and 1d, denoted as D-Val(L) in position 2, show substantial selectivity toward the delta-opioid receptor, while the unsubstituted analogues 1a and 1c, denoted as D-Ala(L) in position 2, bind to both mu- and delta-opioid receptors. The in vivo thermal escape assay by intrathecal administration showed that the analogues 1b and 1d are among the most potent ligands at producing antinociception through the delta-opioid receptor. The picomolar potencies of analogues 1a and 1c in the intrathecal (it.) assay strongly indicate that mu- and delta-opioid receptors interact synergistically to modulate the antinociceptive responses.

Alanine↗
PubMed2002

Receptor-bound conformation of an alpha(5)beta(1) integrin antagonist by (15)N-edited 2D transferred nuclear overhauser effects.

We report the results of (15)N-edited 2D transferred NOE experiments of the partially (15)N-labeled alpha(5)beta(1) antagonist c[Mpa(15)N-Arg-(15)N-Gly-(15)N-Asp-(15)N-Asp-(15)N-Val-Cys]-NH(2) (Mpa denotes mercaptopropionic acid) in the presence of the native alpha(5)beta(1) receptor. The alpha(5)beta(1) integrin receptor is believed to be involved in tumor metastasis and the rational design of alpha(5)beta(1) integrin antagonist is therefore of considerable interest. Our experiments provide insight into the alpha(5)beta(1) receptor-bound conformation of the antagonist c[MpaRGDDVC]-NH2 and will be important for the design of novel antagonists.

Animals↗
PubMed2002

NMR and modeling studies of a synthetic extracellular loop II of the kappa opioid receptor in a DPC micelle.

This paper provides the first direct experimental evidence for the secondary structural features of the putative second extracellular loop (ECL II) of the kappa opioid receptor through a synthetic peptide mimic in a DPC micelle environment. These studies indicate that residues V(6)-A(15) of the ECL II peptide adopt a well-defined helical structure analogous to that formed by V(201)-C(210) of the native receptor. Moreover, a beta-turn around the D(22) (D(217)) and D(23) (D(218)) residues represents another feature of the ECL II. The NMR and fluorescent data also suggest the location of the two helical turns of TM V and the approximate location of the C-terminal end of the TM IV of the kappa opioid receptor. We modeled the kappa opioid receptor including the extracellular region of the receptor. The model of the ECL II utilized the information obtained from the NMR structural analysis of the ECL II peptide in a DPC micelle solution and the molecular dynamic simulations in a biphasic membrane environment. Our discovery of this amphiphilic helical region in the ECL II peptide by NMR and molecular modeling studies provides direct evidence that the sequence of residues V(201)-C(210) is likely to be the helical region that interacts with Dynorphin (Dyn) A [Paterlini, G., Portoghese, P. S., and Ferguson, D. M. (1997) J. Med. Chem. 40, 3254-3262]. We believe that this work offers further insight into the structural characteristics of the extracellular portions of the seven-TM kappa opioid receptor.

Amino Acid Sequence↗
PubMed2002

Studies of the receptor-bound conformation of alphaIIbbeta3 antagonists by 15N-edited NMR spectroscopy.

We report the results of NMR studies and computer simulations of potent antagonists reflective of the alpha(IIb)beta(3) receptor-bound conformations. The peptides c[Mpa-(15)N-Arg(1)-(15)N-Gly(2)-(15)N-Asp(3)-(15)N-Phe(4)-(15)N-Arg(5)-Cys]-NH(2) (Phe-Arg analog) (Mpa: 3-mercaptopropionic acid) and c[Mpa-(15)N-Arg(1)-(15)N-Gly(2)-(15)N-Asp(3)-(15)N-Asp(4)-(15)N-Val(5)-Cys]-NH(2) (Asp-Val analog) were subjected to (15)N-edited NMR experiments to study the conformations of these peptides in the absence and in the presence of alpha(IIb)beta(3) receptor. The NMR studies of the Phe-Arg analog, a selective alpha(IIb)beta(3) antagonist, resulted in distinctly different experimental data in the presence and absence of the receptor. The computer simulations for this peptide resulted in one large family of structures consistent with the experimental data. This conformation suggests a type I beta-turn spanning residues Arg(1) and Gly(2) when bound to the receptor and we were able to establish a model for the three dimensional arrangement of the pharmacophores. The studies on the Asp-Val analog, an alpha(v)beta(3) antagonist that binds to the alpha(IIb)beta(3) with moderate affinity, resulted in conformations that are not as well defined as those for the Phe-Arg analog but are consistent with the model established for this analog. These results are important for the design of novel alpha(IIb)beta(3) antagonists.

Amino Acid Sequence↗
PubMed2002

Incorporation of (2S,3S) and (2S,3R) beta-methyl aspartic acid into RGD-containing peptides.

We report the synthesis and biological activity of a series of side-chain-constrained RGD peptides containing the (2S,3R) or (2S,3S) beta-methyl aspartic acid within the RGD sequence. These compounds have been assayed for binding to the integrin receptors alpha(IIb)beta3 and alpha(v)beta3 and the results demonstrate the importance of the side-chain orientation of this particular residue within the RGD sequence. Based on our findings, the (2S,3S) beta-methylated analogues of our RGD sequences maintain their binding potency to the integrin receptors while the (2S,3R) beta-methylated analogues exhibit a drastically reduced binding affinity. Our studies demonstrate that the three-dimensional orientation of the aspartyl side chain is a very important parameter for integrin binding and that small changes that affect the side-chain orientations give rise to drastic changes in binding affinity. These results provide important information for the design of more potent RGD mimetics.

Aspartic Acid↗