Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Site-Specific and Stoichiometric Stealth Polymer Conjugates of Therapeutic Peptides and Proteins.

ABSTRACT: As potent and selective therapeutic agents, peptides and proteins are an important class of drugs, but they typically have suboptimal pharmacokinetic profiles. One approach to solve this problem is their conjugation with "stealth" polymers. Conventional methods for conjugation of this class of polymers to peptides and proteins are typically carried out by reactions that have poor yield and provide limited control over the site of conjugation and the stoichiometry of the conjugate. To address these limitations, new chemical and biological approaches have been developed that provide new molecular tools in the bioconjugation toolbox to create stealth polymer conjugates of peptides and proteins with exquisite control over their properties. This review article highlights these recent advances in the synthesis of therapeutic peptide- and protein-stealth polymer conjugates.

SUBMITTER: Ozer I

PROVIDER: S-EPMC6372107 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Site-Specific and Stoichiometric Stealth Polymer Conjugates of Therapeutic Peptides and Proteins.

Ozer Imran I Chilkoti Ashutosh A

Bioconjugate chemistry 20170106 3

As potent and selective therapeutic agents, peptides and proteins are an important class of drugs, but they typically have suboptimal pharmacokinetic profiles. One approach to solve this problem is their conjugation with "stealth" polymers. Conventional methods for conjugation of this class of polymers to peptides and proteins are typically carried out by reactions that have poor yield and provide limited control over the site of conjugation and the stoichiometry of the conjugate. To address the ...[more]

PMID: 27998056

Similar Datasets

Site-specific antibody-polymer conjugates for siRNA delivery.

Project description:We describe here the development of site-specific antibody-polymer conjugates (APCs) for the selective delivery of small interference RNAs (siRNAs) to target cells. APCs were synthesized in good yields by conjugating an aminooxy-derivatized cationic block copolymer to an anti-HER2 Fab or full-length IgG by means of genetically encoded p-acetyl phenylalanine (pAcF). The APCs all showed binding affinity comparable to that of HER2 as their native counterparts and no significant cellular cytotoxicity. Mutant S202-pAcF Fab and Q389-pAcF IgG polymer conjugates specifically delivered siRNAs to HER2(+) cells and mediated potent gene silencing at both the mRNA and protein levels. However, a mutant A121-pAcF IgG polymer conjugate, despite its high binding affinity to HER2 antigen, did not induce a significant RNA interference response in HER2(+) cells, presumably due to steric interference with antigen binding and internalization. These results highlight the importance of conjugation site on the activity of antibody-polymer-based therapeutics and suggest that such chemically defined APCs may afford a useful targeted delivery platform for siRNAs or other nucleic acid-based therapies.

| S-EPMC3955097 | biostudies-literature

Site-Specific Zwitterionic Polymer Conjugates of a Protein Have Long Plasma Circulation.

Project description:Many proteins suffer from suboptimal pharmacokinetics (PK) that limit their utility as drugs. The efficient synthesis of polymer conjugates of protein drugs with tunable PK to optimize their in vivo efficacy is hence critical. We report here the first study of the in vivo behavior of a site-specific conjugate of a zwitterionic polymer and a protein. To synthesize the conjugate, we first installed an initiator for atom-transfer radical polymerization (ATRP) at the N?terminus of myoglobin (Mb-N-Br). Subsequently, in situ ATRP was carried out in aqueous buffer to grow an amine-functionalized polymer from Mb-N-Br. The cationic polymer was further derivatized to two zwitterionic polymers by treating the amine groups of the cationic polymer with iodoacetic acid to obtain poly(carboxybetaine methacrylate) with a one-carbon spacer (PCBMA; C1 ), and sequentially with 3-iodopropionic acid and iodoacetic acid to obtain PCBMA(mix) with a mixture of C1 and C2 spacers. The Mb-N-PCBMA polymer conjugates had a longer in vivo plasma half-life than a PEG-like comb polymer conjugate of similar molecular weights (MW). The structure of the zwitterion plays a role in controlling the in vivo behavior of the conjugate, as the PCBMA conjugate with a C1 spacer had significantly longer plasma circulation than the conjugate with a mixture of C1 and C2 spacers.

| S-EPMC4802966 | biostudies-literature

Site-specific conjugation of antifreeze proteins onto polymer-stabilized nanoparticles.

Project description:Antifreeze proteins (AFPs) have many potential applications, ranging from cryobiology to aerospace, if they can be incorporated into materials. Here, a range of engineered AFP mutants were prepared and site-specifically conjugated onto RAFT polymer-stabilized gold nanoparticles to generate new hybrid multivalent ice growth inhibitors. Only the SNAP-tagged AFPs lead to potent 'antifreeze' active nanomaterials with His-Tag capture resulting in no activity, showing the mode of conjugation is essential. This versatile strategy will enable the development of multivalent AFPs for translational and fundamental studies.

| S-EPMC6592154 | biostudies-literature

Therapeutic Peptides Are Preferentially Solubilized in Specific Microenvironments within PEG-PLGA Polymer Nanoparticles.

Project description:Polymeric nanoparticles are a highly promising drug delivery formulation. However, a lack of understanding of the molecular mechanisms that underlie their drug solubilization and controlled release capabilities has hindered the efficient clinical translation of such technologies. Polyethylene glycol-poly(lactic-co-glycolic) acid (PEG-PLGA) nanoparticles have been widely studied as cancer drug delivery vehicles. In this letter, we use unbiased coarse-grained molecular dynamics simulations to model the self-assembly of a PEG-PLGA nanoparticle and its solubulization of the anticancer peptide, EEK, with good agreement with previously reported experimental structural data. We applied unsupervised machine learning techniques to quantify the conformations that polymers adopt at various locations within the nanoparticle. We find that the local microenvironments formed by the various polymer conformations promote preferential EEK solubilization within specific regions of the NP. This demonstrates that these microenvironments are key in controlling drug storage locations within nanoparticles, supporting the rational design of nanoparticles for therapeutic applications.

| S-EPMC10870757 | biostudies-literature

Site-specific enzymatic polysialylation of therapeutic proteins using bacterial enzymes.

Project description:The posttranslational modification of therapeutic proteins with terminal sialic acids is one means of improving their circulating half-life, thereby improving their efficiency. We have developed a two-step in vitro enzymatic modification of glycoproteins, which has previously only been achieved by chemical means [Gregoriadis G, Jain S, Papaioannou I, Laing P (2005) Int J Pharm 300:125-130). This two-step procedure uses the Campylobacter jejuni Cst-II ?2,8-sialyltransferase to provide a primer on N-linked glycans, followed by polysialylation using the Neisseria meningitidis ?2,8-polysialyltransferase. Here, we have demonstrated the ability of this system to modify three glycoproteins with varying N-linked glycan compositions: the human therapeutic proteins alpha-1-antitrypsin (A1AT) and factor IX, as well as bovine fetuin. The chain length of the polysialic acid addition was optimized by controlling reaction conditions. After demonstrating the ability of this system to modify a variety of proteins, the effect of polysialylation on the activity and serum half-life of A1AT was examined. The polysialylation of A1AT did not adversely affect its in vitro inhibition activity against human neutrophil elastase. The polysialylation of A1AT resulted in a significantly improved pharmacokinetic profile when the modified proteins were injected into CD-1 mice. Together, these results suggest that polysialylated A1AT may be useful for improved augmentation therapy for patients with a deficiency in this protein and that this modification may be applied to other therapeutic proteins.

| S-EPMC3088639 | biostudies-literature

Site-specific functionalization of proteins and their applications to therapeutic antibodies.

Project description:Protein modifications are often required to study structure and function relationships. Instead of the random labeling of lysine residues, methods have been developed to (sequence) specific label proteins. Next to chemical modifications, tools to integrate new chemical groups for bioorthogonal reactions have been applied. Alternatively, proteins can also be selectively modified by enzymes. Herein we review the methods available for site-specific modification of proteins and their applications for therapeutic antibodies.

| S-EPMC3995230 | biostudies-literature

Antibody microarrays utilizing site-specific antibody-oligonucleotide conjugates.

Project description:Protein arrays are typically made by random absorption of proteins to the array surface, potentially limiting the amount of properly oriented and functional molecules. We report the development of a DNA encoded antibody microarray utilizing site-specific antibody-oligonucleotide conjugates that can be used for cell immobilization as well as the detection of genes and proteins. This technology allows for the facile generation of antibody microarrays while circumventing many of the drawbacks of conventionally produced antibody arrays. We demonstrate that this method can be used to capture and detect SK-BR-3 cells (Her2+ breast cancer cells) at concentrations as low as 10(2) cells/mL (which is equivalent to 10 cells per 100 ?L array) without the use of microfluidics, which is 100- to 10(5)-fold more sensitive than comparable techniques. Additionally, the method was shown to be able to detect cells in a complex mixture, effectively immobilizing and specifically detecting Her2+ cells at a concentration of 10(2) SK-BR-3 cells/mL in 4 × 10(6) white blood cells/mL. Patients with a variety of cancers can have circulating tumor cell counts of between 1 and 10(3) cells/mL in whole blood, well within the range of this technology.

| S-EPMC4787600 | biostudies-literature

Water-soluble allyl sulfones for dual site-specific labelling of proteins and cyclic peptides.

Project description:Water-soluble allyl sulfones provide convenient site-specific disulfide rebridging of native proteins and cyclic peptides. The site-selective functionalization of (a) the peptide hormone somatostatin, (b) the interchain disulfide of bovine insulin and (c) functionalization of the proteins GFP and lysozyme with allyl sulfones proceeds in aqueous solution. Allyl sulfones offer three functionalizable sites that react with thiol containing molecules in a step-wise fashion. Dual labeling of proteins and cyclic peptides is achieved i.e. the attachment of a chromophore and an affinity tag in a single reaction step, which is of great significance for the construction of precise multifunctional peptide and protein conjugates.

| S-EPMC6006486 | biostudies-literature

Site-specific DNA-antibody conjugates for specific and sensitive immuno-PCR.

Project description:Antibody conjugates are widely used as diagnostics and imaging reagents. However, many such conjugates suffer losses in sensitivity and specificity due to nonspecific labeling techniques. We have developed methodology to site-specifically conjugate oligonucleotides to antibodies containing a genetically encoded unnatural amino acid with orthogonal chemical reactivity. These oligobody molecules were used in immuno-PCR assays to detect Her2(+) cells with greater sensitivity and specificity than nonspecifically coupled fragments, and can detect extremely rare Her2(+) cells in a complex cellular environment. Such designed antibody-oligonucleotide conjugates should provide sensitive and specific reagents for diagnostics, as well as enable other unique applications based on oligobody building blocks.

| S-EPMC3309776 | biostudies-literature

Fibrin specific peptides derived by phage display: characterization of peptides and conjugates for imaging.

Project description:Peptides that bind to fibrin but not to fibrinogen or serum albumin were selected from phage display libraries as targeting moieties for thrombus molecular imaging probes. Three classes of cyclic peptides (cyclized via disulfide bond between two Cys) were identified with consensus sequences XArXCPY(G/D)LCArIX (Ar = aromatic, Tn6), X(2)CXYYGTCLX (Tn7), and NHGCYNSYGVPYCDYS (Tn10). These peptides bound to fibrin at ?2 sites with K(d) = 4.1 ?M, 4.0 ?M, and 8.7 ?M, respectively, whereas binding to fibrinogen was at least 100-fold weaker. The peptides also bind to the fibrin degradation product DD(E) with similar affinity to that measured for fibrin. The Tn7 and Tn10 peptides bind to the same site on fibrin, while the Tn6 peptides bind to a unique site. Alanine scanning identified the N- and C-terminal ends of the Tn6 and Tn7 peptides as most tolerant to modification. Peptide conjugates with either fluorescein or diethylenetriaminepentaaceto gadolinium(III) (GdDTPA) at the N-terminus were prepared for potential imaging applications, and these retained fibrin binding affinity and specificity in plasma. Relaxivity and binding studies on the GdDTPA derivatives revealed that an N-terminal glycyl linker had a modest effect on fibrin affinity but resulted in lower fibrin-bound relaxivity.

| S-EPMC3310290 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data