Oligopeptide Conjugates Research Articles

Role of intramolecular hydrogen bonds in promoting electron flow through amino acid and oligopeptide conjugates

Elucidating the factors that control charge transfer rates in relatively flexible conjugates is of importance for understanding energy flows in biology as well as assisting the design and construction of electronic devices. Here, we report ultrafast electron transfer (ET) and hole transfer (HT) between a corrole (Cor) donor linked to a perylene-diimide (PDI) acceptor by a tetrameric alanine (Ala)4 Selective photoexcitation of the donor and acceptor triggers subpicosecond and picosecond ET and HT. Replacement of the (Ala)4 linker with either a single alanine or phenylalanine does not substantially affect the ET and HT kinetics. We infer that electronic coupling in these reactions is not mediated by tetrapeptide backbone nor by direct donor-acceptor interactions. Employing a combination of NMR, circular dichroism, and computational studies, we show that intramolecular hydrogen bonding brings the donor and the acceptor into proximity in a "scorpion-shaped" molecular architecture, thereby accounting for the unusually high ET and HT rates. Photoinduced charge transfer relies on a (Cor)NH…O=C-NH…O=C(PDI) electronic-coupling pathway involving two pivotal hydrogen bonds and a central amide group as a mediator. Our work provides guidelines for construction of effective donor-acceptor assemblies linked by long flexible bridges as well as insights into structural motifs for mediating ET and HT in proteins.

Oligopeptide-targeted polymer nanoprobes for fluorescence-guided endoscopic surgery

A polymer probe based on N-(2-hydroxypropyl)methacrylamide copolymers labelled with a fluorescent dye Dy-633 or Cy-7 and decorated with targeting oligopeptides GE-7 or GE-11, specific targeting ligands binding to epidermal growth factor receptor (EGFR) highly expressed on surface of tumour cells, was designed, synthesised and characterised. Specific accumulation of the polymer probe in the tumour mass is a prerequisite for successful fluorescence-guided endoscopic surgery as the fluorescence signal from the malignant cells enables more precise resection of the tumour without damaging the healthy tissue. Flow cytometry and confocal microscopy was used to assess the binding efficacy of the oligopeptide conjugates to EGFR on the cell membranes of the malignant cells. The results showed that the highest binding efficacy was achieved with polymers bearing the GE-11 targeting oligopeptide in human EGFR-positive hypopharyngeal carcinoma cells (FaDu) and in breast adenocarcinoma cells (MDA-MB-231). Similarly, the polymer probes targeted by the GE-11 oligopeptidewere found in vivo as highly effective in tumour accumulation, as determined from fluorescence imaging. Indeed, the ex vivo cross-section of the tumours showed significant tumour border fluorescence proving the potential of the studied polymer probes. Moreover, the presence of the active targeting moiety on the polymer-drug conjugate should enable the use of such a conjugate as a targeted polymer system for treatment of solid tumours. Replacement of the fluorescent probe with a cytostatic drug provides a targeted polymer nanocancerostatic for advanced treatment of neoplastic diseases, thus the polymer probes have multiple functions.

Oligo-aspartic acid conjugates with benzo[c][2,6]naphthyridine-8-carboxylic acid scaffold as picomolar inhibitors of CK2

Structurally diverse inhibitors of the protein kinase CK2 are required for regulation of this ubiquitous protein to establish biological roles of the enzyme which catalyzes the phosphorylation of a vast number of substrate proteins. In this article we disclose a series of new bisubstrate inhibitors of CK2 that are structurally represented by the oligo(l-Asp) peptide conjugates of benzo[c][2,6]naphthyridine-8-carboxylic acid. This fragment originated from CX-4945, the first in class inhibitor taken to clinical trials. The most potent conjugates possessed two-digit picomolar affinity and clear selectivity for CK2α in a panel of 140 protein kinases. Labeling of the inhibitors with a fluorescent dye yielded probes for a fluorescence anisotropy-based binding/displacement assay which can be used for analysis of CK2 and precise determination of affinity of the highly potent (tight-binding) CK2-targeting inhibitors.

Multi-responsive supramolecular hydrogels based on merocyanine-peptide conjugates.

Stimuli-responsive hydrogels are "smart" materials with diverse applications. We now report short peptide conjugates with merocyanine (MC) that are able to form stimuli-responsive hydrogels. Systematic investigation reveals that merocyanine is a highly effective promoter for the self-assembly of its oligopeptide conjugates. Hydrogels formed by MC-peptide conjugates showed responses towards light and heat, and their sol-gel phase transition could be manipulated by the reverse photochromism of the corresponding spiropyran moiety. Impressively, a MCI-RGD conjugate formed a supramolecular hydrogel with responses to multiple stimuli, including visible light irradiation, pH change and the presence of Ca(2+) ions. An erasable photo-lithograph on the MCI-RGD hydrogel was demonstrated using visible light to write and heat-and-cool treatment to erase for multiple rounds without significant loss of sensitivity.

10th Annual Meeting of the Oligonucleotide Therapeutics Society

Nucleic Acid TherapeuticsVol. 24, No. 6 Meeting Report10th Annual Meeting of the Oligonucleotide Therapeutics SocietySan Diego, California | October 12–15, 2014Session SummariesKeith T. Gagnon, Jonathan K. Watts, and on behalf of the Board of the Oligonucleotide Therapeutics SocietyKeith T. GagnonSearch for more papers by this author, Jonathan K. WattsSearch for more papers by this author, and on behalf of the Board of the Oligonucleotide Therapeutics SocietySearch for more papers by this authorPublished Online:3 Dec 2014https://doi.org/10.1089/nat.2014.1502AboutSectionsView articleView Full TextPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View articleFiguresReferencesRelatedDetailsCited ByAdvances in Nanoparticle Drug Delivery Systems for Anti-Hepatitis B Virus Therapy: A Narrative Review18 October 2021 | International Journal of Molecular Sciences, Vol. 22, No. 20Chemical Synthesis and Biological Application of Modified Oligonucleotides31 March 2020 | Bioconjugate Chemistry, Vol. 31, No. 5The chemical evolution of oligonucleotide therapies of clinical utility27 February 2017 | Nature Biotechnology, Vol. 35, No. 3Inhibition of hepatitis C virus in mouse models by lipidoid nanoparticle-mediated systemic delivery of siRNA against PRK2Nanomedicine: Nanotechnology, Biology and Medicine, Vol. 12, No. 6The role of helper lipids in lipid nanoparticles (LNPs) designed for oligonucleotide deliveryAdvanced Drug Delivery Reviews, Vol. 99Inhibition of Hepatitis C Virus in Mice by a Small Interfering RNA Targeting a Highly Conserved Sequence in Viral IRES Pseudoknot11 January 2016 | PLOS ONE, Vol. 11, No. 1Emerging Advances in the Management of Cardiac Amyloidosis15 September 2015 | Current Cardiology Reports, Vol. 17, No. 11Oligonucleotide therapeutics: chemistry, delivery and clinical progressFuture Medicinal Chemistry, Vol. 7, No. 16Concise postsynthetic preparation of oligonucleotide–oligopeptide conjugates through facile disulfide bond formationFuture Medicinal Chemistry, Vol. 7, No. 13Hepatitis B virus therapy: What’s the future holding for us?World Journal of Gastroenterology, Vol. 21, No. 44 Volume 24Issue 6Dec 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Keith T. Gagnon, Jonathan K. Watts, and on behalf of the Board of the Oligonucleotide Therapeutics Society.10th Annual Meeting of the Oligonucleotide Therapeutics Society.Nucleic Acid Therapeutics.Dec 2014.428-434.http://doi.org/10.1089/nat.2014.1502Published in Volume: 24 Issue 6: December 3, 2014PDF download

Novel Dendritic Naproxen Prodrugs with Poly(aspartic Acid) Oligopeptide: Synthesis and Hydroxyapatite Binding in Vitro

Novel bone-targeting prodrugs containing dendritic naproxen and poly(aspartic acid) oligopeptide were synthesized in a convergent approach and were characterized by NMR, mass spectral, and elemental analysis techniques. The modified naproxen prodrugs showed a high affinity to hydroxyapatite in vitro and provided an effective entry for the synthesis of a dendritic naproxen–poly(aspartic acid) oligopeptide conjugates used for bone targeting.

Syntheses of [12]aneN3–oligopeptide conjugates as effective DNA condensation agents

With the aim to develop effective and low toxicity DNA condensation agents, a series of oligopeptide derived macrocyclic polyamine [12]aneN3 conjugates 7a–h·3HCl have been designed and synthesized through multi-step amidation reactions. Structure–property study through gel electrophoresis proved that the conjugates containing high hydrophobic ending amino acids exhibited effective condensation ability at concentration of 150–250μM, which was further confirmed by dynamic light scattering and atomic force microscopy experiments. EB displacement assay, ionic salt effect, and structure–property relationship in gel electrophoresis indicated that DNA condensation resulted from both the electrostatic interaction of [12]aneN3 unit and hydrogen-bonding/hydrophobic multi-interaction of oligopeptide moiety in the conjugates with DNA. The reversible condensation process and their low cytotoxicity suggest that the new condensing agents are potential for the development of non-viral vectors.

Triggered Cargo Release by Encapsulated Enzymatic Catalysis in Capsosomes

We report the coencapsulation of glutathione reductase and disulfide-linked polymer-oligopeptide conjugates into capsosomes, polymer carrier capsules containing liposomal subcompartments. The architecture of the capsosomes enables a temperature-triggered conversion of oxidized glutathione to its reduced sulfhydryl form by the encapsulated glutathione reductase. The reduced glutathione subsequently induces the release of the encapsulated oligopeptides from the capsosomes by reducing the disulfide linkages of the conjugates. This study highlights the potential of capsosomes to continuously generate a potent antioxidant while simultaneously releasing small molecule therapeutics.

Polyoligopeptides functionalized zinc(II)porphyrins: Step towards artificial hemes

Two new zinc(II)porphyrin oligopeptide conjugates (zinc(II)-5,10,15,20-bis[4-(peptide)- phenyl]porphyrin (5) and -tetrakis[3,5-di(peptide)phenyl]porphyrin (9; peptide = -CH2(CO)Gly-Phe-Ala-CNH2) were prepared using the click chemistry with azides and ethynyl-containing precursors. The spectroscopic signature (S0→S1 and transient T1→Tn absorption, excitation and emission spectra) are typical for zinc(II)porphyrin and shows no perturbation upon anchoring the oligopeptides, whereas some small decreases in the photophysical parameters (𝜏F and ΦF), and larger decrease in T1 lifetimes are noted, which are attributable to the known "loose bolt" effect. The structure for 9 in solution was addressed qualitatively using computer modeling and the comparison of the bimolecular fluorescence quenching rate constants between 5 and 9 using C60 as a photooxidative agent. While 5 exhibits a totally accessible zinc(II)porphyrin unit for a C60 approach, 9 shows a slower quenching rate constant meaning some steric hindrance must be present.

Synthesis and Self-Assembly of Oligo(p-phenylenevinylene) Peptide Conjugates in Water

Synthesis and Self-Assembly of Oligo(p-phenylenevinylene) Peptide Conjugates in Water

Controlled growth of silver nanoparticle arrays guided by a self-assembled polymer–peptide conjugate

Controlled formation of silver nanoparticle arrays with high particle density and short interparticle distances was achieved by using supramolecular nanotapes of PEO–oligopeptide conjugates as templates to direct the nucleation and growth of silver nanoparticles either from silver salt solutions followed by photoreduction, or from preformed fluorescent silver nanoclusters.

Synthesis and in Vitro Hydroxyapatite Binding of Peptides Conjugated to Calcium-Binding Moieties

To confer bone-binding properties to proteins and other biological agents that lack specific targeting capacity, model peptide-based molecules were synthesized containing poly(aspartic acid), poly(glutamic acid), or a bisphosphonate (pamidronate). These motifs have well-documented affinities to hydroxyapatite, a property desirable for the targeting of molecules to bone for drug delivery and tissue engineering applications. Model peptides of increasing molecular mass (5-33 amino acids) were directly conjugated to eight aspartic acids (Asp8), eight glutamic acids (Glu8), or pamidronate, purified by high-performance liquid chromatography, and characterized by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectroscopy. The modified peptides were incubated with hydroxyapatite in phosphate-buffered saline at physiological conditions over 24 h. This study revealed a significant amount (>90%) of conjugated peptides adsorbed to the hydroxyapatite as compared to unmodified peptides (<5%). It was found that while there were significant differences between the different hydroxyapatite-binding and control groups for all time points, the size of the peptide had no statistical effect on peptide-hydroxyapatite binding. These results demonstrate that bisphosphonate and oligopeptide conjugates hold great promise for the development of new bioactive molecules for bone-specific applications.

New ferrocene containing peptide conjugates: Synthesis and effect on human leukemia (HL‐60) cells

Data reported in this article describe the synthesis of Arg-rich oligopeptide conjugates of ferrocenecarboxylic acid on solid support with two different strategies and for the first time, the successful preparation of peptide conjugates of ferrocenylacrylic acid in solution. The antitumor effect of conjugates was analyzed by MTT assay in vitro. We demonstrated that ferrocenylacrylic acid possessing an enone (--CH==CH--CO--) moiety exhibited remarkable antiproliferative effect against human leukemia cells (HL-60) in vitro, but its effect was not improved by conjugation with hexa- or octaarginines. However, we observed highly increased water-solubility. In contrast, the results provide evidence that conjugation of ferrocenecarboxylic acid to Arg(n) (n = 6, 8) improved not only its water-solubility, but also antitumor effect on human leukemia cells in vitro.

Bile Acid−Oligopeptide Conjugates Interact with DNA and Facilitate Transfection

Bile acids conjugated to oligoarginine-containing peptides (BACs) form complexes with DNA based on the electrostatic interactions between negatively charged phosphate groups of the nucleic acid and the positively charged side chain guanidinium groups of the oligoarginine in the BACs. Charge neutralization of both components and subsequent increases of the net positive charge of the complex combined with the water-soluble lipophilic nature of the bile acid results in changes in the physicochemistry and biological properties of the complexes. We have examined the relationship of a series of 13 BACs on their interaction with circular plasmid DNA (pDNA). The formation of soluble, low-density and insoluble, high-density complexes was analyzed using several methods. The formation of high-density complexes was dependent on the DNA concentration, and was enhanced by increasing the BAC to pDNA charge ratio. Several of the BAC:pDNA complexes demonstrated exclusion of the DNA-intercalator Hoechst 33258 from pDNA, and were also protected from DNase activity. Several BAC conjugates interacted with pDNA to form nanometer-sized particles suitable for cell transfection in vitro. Five of the 13 BACs were transfection competent as single agents, and 11 of the 13 BACs showed enhancement of transfection in combination with DOPE containing liposomes or silica nanoparticles.

Synthesis and spectroscopic properties of 4-ethoxymethylene-2-(1)-naphthyl-5(4H)-oxazolone-labeled fluorescent peptides

Strategies for the preparation of new fluorescent oligopeptide conjugates labeled with 4-ethoxymethylene-2-[1]-naphthyl-5(4H)-oxazolone (naOx-OEt) at the N-terminal on solid support or in solution have been devised. These procedures are simple and easy to carry out by reacting naOx-OEt or N(alpha)-naOx-amino acid with side chain protected peptide chains attached to resins. The integrity of the N-alkyl bond was maintained even after the trifluoracetic acid or HF based cleavages procedures. Our data show that the naOx fluorophore is compatible with both Fmoc/tBu and Boc/Bzl methods and also suggest that naOx-amino acid could be utilized as building blocks for solid phase peptide synthesis. Comparative analysis of fluorescence properties of naOx-conjugates indicated that the spectral properties of the fluorophore do not change after incorporating into peptides. The compact size, the definite chemical reaction for its introduction in combination with the appropriate spectral features (e.g., intense emission, pH independent fluorescent characteristics, and beneficial photobleaching dose constant and rates) and with chemical and spectral stability, naOx-based labeling could be attractive for novel cellular fluorescent techniques (e.g., in laser scanning confocal FRET) to study peptide-protein and protein-protein interactions even in biological matrices.

Synthesis of oligotuftsin-based branched oligopeptide conjugates for chemotactic drug targeting

The synthesis and chemotactic properties of a new class of branched oligopeptide-based conjugates are described. Tetratuftsin derivatives containing chemotactic formyl tripeptides (For-MLF, For-NleLF or For-MMM) in branches were prepared by stepwise solid-phase peptide synthesis. The influence of the composition and ionic charge of the carrier-branched oligopeptide on the chemotactic behaviour of the conjugate was studied in Tetrahymena pyriformis. Conjugates with methotrexate (Mtx) as a drug component was also prepared. For this, a GFLGC spacer, cleavable by cathepsin B, was used. The spacer with N-terminal methotrexate was coupled to the chloroacetylated chemotactic carrier molecule by thioether bond formation. The chemotactic activity and cytotoxity of Mtx conjugates were also studied.

Synthesis and immunochemical characterization of protein conjugates of carbohydrate and carbohydrate-mimetic peptides as experimental vaccines

The peptides DRPVPY and MDWNMHAA, which were identified as mimics of the cell-surface polysaccharides of Streptococcus Group A and Shigella flexneri Y, respectively, were used in this study to develop experimental vaccines directed against these two bacteria. Both oligopeptides were synthesized employing the Fmoc solid-phase strategy and linked via the amino end to a bifunctional linker, diethylsquarate. These adducts were then conjugated to the two carrier proteins, bovine serum albumin (BSA) and tetanus toxoid (TT) to yield the peptide conjugate vaccines. The average level of incorporation of DRPVPY and MDWNMHAA on TT was 65% and 75%, respectively, whereas that of both peptide haptens on BSA was 100%. A polysaccharide conjugate against S. flexneri Y, which comprises about 10 tetrasaccharide repeating units, was also prepared based on reductive amination at the reducing end with 1,3-diaminopropane, followed by coupling of the aminated polysaccharide to diethylsquarate, and subsequent coupling of the adduct to TT. An average incorporation of 73% of polysaccharide haptens was achieved. The glycoconjugate and the oligopeptide conjugates were shown to bind effectively to the respective monoclonal antibodies directed against the cell-surface polysaccharides.

Introduction of Lanthanide(III) Chelates to Oligopeptides on Solid Phase

The synthesis of oligopeptide building blocks for the introduction of nonluminescent and luminescent lanthanide(III) chelates to the oligopeptide structure on the solid phase is described. The oligopeptide conjugates synthesized were used in DELFIA-based receptor binding assay (motilin) as well as in LANCE time-resolved fluorescence quenching assay (caspase-3).

Novel water-soluble porphyrin-based receptors for saccharide recognition

A binding study of porphyrin phosphonates ( 1, 2), porphyrin–oligopeptide conjugates ( 3– 5), porphyrin–fluorescein ( 6), and porphyrin–methyl red ( 7) conjugates to saccharides and alkyl pyranosides showed strong interaction in aqueous media and DMSO. The UV–Vis, fluorescence, 1H-, 31P-NMR, and IR spectroscopy were used to study the mechanisms of complexation. Participation of hydrogen bonds in the formation of porphyrin–saccharide complexes was demonstrated.

Novel porphyrin based receptors for saccharide recognition in water

A binding study of the porphyrin phosphonates ( 1, 2), porphyrin–oligopeptide conjugates ( 3– 5) and meso-tetrakis-( p-sulfonato-phenyl) porphyrin ( 7) to saccharides and alkyl pyranosides showed strong interaction in water and DMSO. The 1 H , 31 P NMR, IR-spectroscopy and SPR technique were used for the study of mechanisms of complexation and potential using of receptors as sensor part; participant of hydrogen bonds in porphyrin–saccharide complexes formation was demonstrated.