Site-Specific Growth of Stealth Polymer from Peptide Therapeutics View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2011-2015

FUNDING AMOUNT

1310975 USD

ABSTRACT

DESCRIPTION (provided by applicant): The delivery of therapeutic proteins and peptides in their unmodified form has several limitations, which include poor stability, low solubility, short in vivo circulation, and immunogenicity. Although conjugating proteins and peptides with polyethylene glycol (PEG) -termed PEGylation- is one strategy to overcome these limitations, PEGylation of native proteins or peptides provides limited control of the conjugation site and poor control of stoichiometry because of the promiscuous distribution of common reactive side chains on the surface of most proteins; alternative methods to specify a unique conjugation site on the protein require protein engineering and/or incorporation of bioorthogonal unnatural amino acids to create mutant proteins, which is typically a protein specific exercise and alters the composition of the biological drug. Furthermore, in both these approaches, the attachment of presynthesized PEG to the native or mutant protein typically proceeds with low yield because of steric repulsion between these water-soluble macromolecules. Motivated by these limitations, the overall objective of this NIH R01 research proposal is two-fold: the first objective is to develop a new polymer conjugation methodology by the in situ growth of a protein-resistant stealth polymer, poly(oligoethylene glycol methacrylate) (POEGMA), exclusively from the N- or C-terminus -the only two conserved reactive sites in a polypeptide sequence- in aqueous buffer by atom transfer radical transfer polymerization (ATRP) with high yield and good control of polymer chain length. We call this methodology InStealth conjugation (in situ growth of stealth polymer), and it yields site- specific stoichiometric conjugates of a PEG-like polymer with tunable molecular weight. The second, related objective is to demonstrate the utility of the InStealth technology to improve the pharmacological profile of a peptide drug -Exendin- that is currently used to treat type II diabetes, but which has fast clearance and poor bioavailability. The impact of these studies will be demonstration of the InStealth conjugation technology as a potentially broadly applicable polymer conjugation technology for the sustained delivery of peptide and protein drugs that overcomes the problems associated with PEGylation. More... »

URL

http://projectreporter.nih.gov/project_info_description.cfm?aid=8721945

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/2203", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "type": "DefinedTerm"
      }
    ], 
    "amount": {
      "currency": "USD", 
      "type": "MonetaryAmount", 
      "value": "1310975"
    }, 
    "description": "DESCRIPTION (provided by applicant): The delivery of therapeutic proteins and peptides in their unmodified form has several limitations, which include poor stability, low solubility, short in vivo circulation, and immunogenicity. Although conjugating proteins and peptides with polyethylene glycol (PEG) -termed PEGylation- is one strategy to overcome these limitations, PEGylation of native proteins or peptides provides limited control of the conjugation site and poor control of stoichiometry because of the promiscuous distribution of common reactive side chains on the surface of most proteins; alternative methods to specify a unique conjugation site on the protein require protein engineering and/or incorporation of bioorthogonal unnatural amino acids to create mutant proteins, which is typically a protein specific exercise and alters the composition of the biological drug. Furthermore, in both these approaches, the attachment of presynthesized PEG to the native or mutant protein typically proceeds with low yield because of steric repulsion between these water-soluble macromolecules. Motivated by these limitations, the overall objective of this NIH R01 research proposal is two-fold: the first objective is to develop a new polymer conjugation methodology by the in situ growth of a protein-resistant stealth polymer, poly(oligoethylene glycol methacrylate) (POEGMA), exclusively from the N- or C-terminus -the only two conserved reactive sites in a polypeptide sequence- in aqueous buffer by atom transfer radical transfer polymerization (ATRP) with high yield and good control of polymer chain length. We call this methodology InStealth conjugation (in situ growth of stealth polymer), and it yields site- specific stoichiometric conjugates of a PEG-like polymer with tunable molecular weight. The second, related objective is to demonstrate the utility of the InStealth technology to improve the pharmacological profile of a peptide drug -Exendin- that is currently used to treat type II diabetes, but which has fast clearance and poor bioavailability. The impact of these studies will be demonstration of the InStealth conjugation technology as a potentially broadly applicable polymer conjugation technology for the sustained delivery of peptide and protein drugs that overcomes the problems associated with PEGylation.", 
    "endDate": "2015-08-31T00:00:00Z", 
    "funder": {
      "id": "https://www.grid.ac/institutes/grid.419635.c", 
      "type": "Organization"
    }, 
    "id": "sg:grant.2500476", 
    "identifier": [
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "2500476"
        ]
      }, 
      {
        "name": "nih_id", 
        "type": "PropertyValue", 
        "value": [
          "R01DK092665"
        ]
      }
    ], 
    "inLanguage": [
      "en"
    ], 
    "keywords": [
      "alternative method", 
      "immunogenicity", 
      "aqueous buffer", 
      "Peptide Therapeutics", 
      "stealth polymer", 
      "limited control", 
      "radical transfer polymerization", 
      "NIH R01 research proposal", 
      "common reactive side chains", 
      "applicants", 
      "poor stability", 
      "most proteins", 
      "description", 
      "strategies", 
      "atom transfer", 
      "water-soluble macromolecules", 
      "biological drugs", 
      "protein engineering", 
      "conjugation site", 
      "unmodified form", 
      "several limitations", 
      "surface", 
      "polypeptide sequence-", 
      "mutant proteins", 
      "delivery", 
      "poor bioavailability", 
      "low solubility", 
      "poor control", 
      "situ growth", 
      "peptides", 
      "high yields", 
      "composition", 
      "InStealth technology", 
      "study", 
      "fast clearance", 
      "attachment", 
      "POEGMA", 
      "polyethylene glycol", 
      "PEGylation-", 
      "unique conjugation site", 
      "utility", 
      "overall objective", 
      "better control", 
      "protein-resistant stealth polymer", 
      "native protein", 
      "pharmacological profile", 
      "InStealth conjugation technology", 
      "type II diabetes", 
      "applicable polymer conjugation technology", 
      "demonstration", 
      "approach", 
      "specific exercises", 
      "therapeutic proteins", 
      "limitations", 
      "first objective", 
      "new polymer conjugation methodology", 
      "incorporation", 
      "two-fold", 
      "poly(oligoethylene glycol methacrylate", 
      "N-", 
      "PEG-like polymer", 
      "site-specific growth", 
      "bioorthogonal unnatural amino acids", 
      "stoichiometry", 
      "PEGylation", 
      "terminus -the", 
      "methodology InStealth conjugation", 
      "sustained delivery", 
      "steric repulsion", 
      "specific stoichiometric conjugates", 
      "low yield", 
      "protein drugs", 
      "reactive sites", 
      "promiscuous distribution", 
      "tunable molecular weights", 
      "impact", 
      "vivo circulation", 
      "protein", 
      "polymer chain length", 
      "related objectives", 
      "problem", 
      "peptide drug -Exendin-"
    ], 
    "name": "Site-Specific Growth of Stealth Polymer from Peptide Therapeutics", 
    "recipient": [
      {
        "id": "https://www.grid.ac/institutes/grid.26009.3d", 
        "type": "Organization"
      }, 
      {
        "affiliation": {
          "id": "https://www.grid.ac/institutes/grid.26009.3d", 
          "name": "DUKE UNIVERSITY", 
          "type": "Organization"
        }, 
        "familyName": "CHILKOTI", 
        "givenName": "ASHUTOSH", 
        "id": "sg:person.01051674744.73", 
        "type": "Person"
      }, 
      {
        "member": "sg:person.01051674744.73", 
        "roleName": "PI", 
        "type": "Role"
      }
    ], 
    "sameAs": [
      "https://app.dimensions.ai/details/grant/grant.2500476"
    ], 
    "sdDataset": "grants", 
    "sdDatePublished": "2019-03-07T12:16", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com.uberresearch.data.processor/core_data/20181219_192338/projects/base/nih_projects_8.xml.gz", 
    "startDate": "2011-09-30T00:00:00Z", 
    "type": "MonetaryGrant", 
    "url": "http://projectreporter.nih.gov/project_info_description.cfm?aid=8721945"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/grant.2500476'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/grant.2500476'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/grant.2500476'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/grant.2500476'


 

This table displays all metadata directly associated to this object as RDF triples.

126 TRIPLES      19 PREDICATES      104 URIs      96 LITERALS      5 BLANK NODES

Subject Predicate Object
1 sg:grant.2500476 schema:about anzsrc-for:2203
2 schema:amount N6e1202ba01e64ff1b5013d99181fe1aa
3 schema:description DESCRIPTION (provided by applicant): The delivery of therapeutic proteins and peptides in their unmodified form has several limitations, which include poor stability, low solubility, short in vivo circulation, and immunogenicity. Although conjugating proteins and peptides with polyethylene glycol (PEG) -termed PEGylation- is one strategy to overcome these limitations, PEGylation of native proteins or peptides provides limited control of the conjugation site and poor control of stoichiometry because of the promiscuous distribution of common reactive side chains on the surface of most proteins; alternative methods to specify a unique conjugation site on the protein require protein engineering and/or incorporation of bioorthogonal unnatural amino acids to create mutant proteins, which is typically a protein specific exercise and alters the composition of the biological drug. Furthermore, in both these approaches, the attachment of presynthesized PEG to the native or mutant protein typically proceeds with low yield because of steric repulsion between these water-soluble macromolecules. Motivated by these limitations, the overall objective of this NIH R01 research proposal is two-fold: the first objective is to develop a new polymer conjugation methodology by the in situ growth of a protein-resistant stealth polymer, poly(oligoethylene glycol methacrylate) (POEGMA), exclusively from the N- or C-terminus -the only two conserved reactive sites in a polypeptide sequence- in aqueous buffer by atom transfer radical transfer polymerization (ATRP) with high yield and good control of polymer chain length. We call this methodology InStealth conjugation (in situ growth of stealth polymer), and it yields site- specific stoichiometric conjugates of a PEG-like polymer with tunable molecular weight. The second, related objective is to demonstrate the utility of the InStealth technology to improve the pharmacological profile of a peptide drug -Exendin- that is currently used to treat type II diabetes, but which has fast clearance and poor bioavailability. The impact of these studies will be demonstration of the InStealth conjugation technology as a potentially broadly applicable polymer conjugation technology for the sustained delivery of peptide and protein drugs that overcomes the problems associated with PEGylation.
4 schema:endDate 2015-08-31T00:00:00Z
5 schema:funder https://www.grid.ac/institutes/grid.419635.c
6 schema:identifier N00a880bc77394eb59c9fa395a5e65b94
7 N6ee0ae70a25448e191626bbf18bcdcf2
8 schema:inLanguage en
9 schema:keywords InStealth conjugation technology
10 InStealth technology
11 N-
12 NIH R01 research proposal
13 PEG-like polymer
14 PEGylation
15 PEGylation-
16 POEGMA
17 Peptide Therapeutics
18 alternative method
19 applicable polymer conjugation technology
20 applicants
21 approach
22 aqueous buffer
23 atom transfer
24 attachment
25 better control
26 biological drugs
27 bioorthogonal unnatural amino acids
28 common reactive side chains
29 composition
30 conjugation site
31 delivery
32 demonstration
33 description
34 fast clearance
35 first objective
36 high yields
37 immunogenicity
38 impact
39 incorporation
40 limitations
41 limited control
42 low solubility
43 low yield
44 methodology InStealth conjugation
45 most proteins
46 mutant proteins
47 native protein
48 new polymer conjugation methodology
49 overall objective
50 peptide drug -Exendin-
51 peptides
52 pharmacological profile
53 poly(oligoethylene glycol methacrylate
54 polyethylene glycol
55 polymer chain length
56 polypeptide sequence-
57 poor bioavailability
58 poor control
59 poor stability
60 problem
61 promiscuous distribution
62 protein
63 protein drugs
64 protein engineering
65 protein-resistant stealth polymer
66 radical transfer polymerization
67 reactive sites
68 related objectives
69 several limitations
70 site-specific growth
71 situ growth
72 specific exercises
73 specific stoichiometric conjugates
74 stealth polymer
75 steric repulsion
76 stoichiometry
77 strategies
78 study
79 surface
80 sustained delivery
81 terminus -the
82 therapeutic proteins
83 tunable molecular weights
84 two-fold
85 type II diabetes
86 unique conjugation site
87 unmodified form
88 utility
89 vivo circulation
90 water-soluble macromolecules
91 schema:name Site-Specific Growth of Stealth Polymer from Peptide Therapeutics
92 schema:recipient N55326518260b404ba1eee0213e105159
93 sg:person.01051674744.73
94 https://www.grid.ac/institutes/grid.26009.3d
95 schema:sameAs https://app.dimensions.ai/details/grant/grant.2500476
96 schema:sdDatePublished 2019-03-07T12:16
97 schema:sdLicense https://scigraph.springernature.com/explorer/license/
98 schema:sdPublisher N3cdebc7f4519459dacb898d0670a2e2e
99 schema:startDate 2011-09-30T00:00:00Z
100 schema:url http://projectreporter.nih.gov/project_info_description.cfm?aid=8721945
101 sgo:license sg:explorer/license/
102 sgo:sdDataset grants
103 rdf:type schema:MonetaryGrant
104 N00a880bc77394eb59c9fa395a5e65b94 schema:name nih_id
105 schema:value R01DK092665
106 rdf:type schema:PropertyValue
107 N3cdebc7f4519459dacb898d0670a2e2e schema:name Springer Nature - SN SciGraph project
108 rdf:type schema:Organization
109 N55326518260b404ba1eee0213e105159 schema:member sg:person.01051674744.73
110 schema:roleName PI
111 rdf:type schema:Role
112 N6e1202ba01e64ff1b5013d99181fe1aa schema:currency USD
113 schema:value 1310975
114 rdf:type schema:MonetaryAmount
115 N6ee0ae70a25448e191626bbf18bcdcf2 schema:name dimensions_id
116 schema:value 2500476
117 rdf:type schema:PropertyValue
118 anzsrc-for:2203 schema:inDefinedTermSet anzsrc-for:
119 rdf:type schema:DefinedTerm
120 sg:person.01051674744.73 schema:affiliation https://www.grid.ac/institutes/grid.26009.3d
121 schema:familyName CHILKOTI
122 schema:givenName ASHUTOSH
123 rdf:type schema:Person
124 https://www.grid.ac/institutes/grid.26009.3d schema:name DUKE UNIVERSITY
125 rdf:type schema:Organization
126 https://www.grid.ac/institutes/grid.419635.c schema:Organization
 




Preview window. Press ESC to close (or click here)


...