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CXCR4 targeted peptide carriers for the inhibition of HIV and delivery of anti-viral drugs
Descriptive
TitleInfo
Title
CXCR4 targeted peptide carriers for the inhibition of HIV and delivery of anti-viral drugs
Name
(type = personal)
NamePart
(type = family)
Palombo
NamePart
(type = given)
Matthew S.
NamePart
(type = date)
1982-
DisplayForm
Matthew Palombo
Role
RoleTerm
(authority = RULIB)
author
Name
(type = personal)
NamePart
(type = family)
Sinko
NamePart
(type = given)
Patrick J
DisplayForm
Patrick J Sinko
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
chair
Name
(type = personal)
NamePart
(type = family)
Uhrich
NamePart
(type = given)
Kathryn
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Kathryn Uhrich
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Hatefi
NamePart
(type = given)
Arash
DisplayForm
Arash Hatefi
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
internal member
Name
(type = personal)
NamePart
(type = family)
Su
NamePart
(type = given)
Yaming
DisplayForm
Yaming Su
Affiliation
Advisory Committee
Role
RoleTerm
(authority = RULIB)
outside member
Name
(type = corporate)
NamePart
Rutgers University
Role
RoleTerm
(authority = RULIB)
degree grantor
Name
(type = corporate)
NamePart
Graduate School - New Brunswick
Role
RoleTerm
(authority = RULIB)
school
TypeOfResource
Text
Genre
(authority = marcgt)
theses
OriginInfo
DateCreated
(qualifier = exact)
2013
DateOther
(qualifier = exact);
(type = degree)
2013-05
Place
PlaceTerm
(type = code)
xx
Language
LanguageTerm
(authority = ISO639-2b);
(type = code)
eng
Abstract
(type = abstract)
HIV-1 continues to be a major epidemic affecting the global population and responsible for millions of deaths annually. Despite the mortality of the virus, great improvement in the currently available retroviral pharmacotherapy has lead to a chronic treatment of infected individuals. However the current therapy is not a cure for HIV-1 infection and eventually drug resistant viral strains will deplete the infected individual of CD4+ T cells. The chemokine receptor CXCR4 plays an important role to HIV-1 infection of host cells. CXCR4 acts as a coreceptor to viral entry. CXCR4 is expressed several types of HIV-1 susceptible cells and therefore has been identified as a target for anti-viral intervention as well as a targeted drug delivery system. The thesis herein is focused developing peptide drug conjugates targeting CXC4. Peptide carriers were synthesized to specifically interact with CXCR4 by the targeting sequence DV3. Multivalent DV3 peptide carriers containing 1, 2, or 4 copies of the CXCR4 targeting sequence DV3 were tested in vitro for the inhibition of HIV-1 entry and cellular uptake via confocal microscopy. Only the 4 copy DV3 peptide carriers (4DV3) significantly inhibited HIV-1 from infecting the reporter cell line TZM-bl and were entrapped within cellular endosomes. 4DV3 inhibited the HIV-1 strain IIIB in vitro (IC50=553nM). The small molecule, AMD3100 (47%), and a CXCR4 monoclonal antibody (IC50 = 398nM) inhibited the 4DV3/CXCR4 interaction. Molecular modeling of 4DV3 interacting with CXCR4 demonstrated the ability of 4DV3 to interact with a tetramer of the receptor. 4DV3 was further modified to carry drug cargoes with known anti-viral activity. Comparative analysis of the peptides carrier’s ability to enhance the anti-HIV activity of the drug, the 4DV3, or act synergistically was investigated. 4DV3 conjugates of AZT (IC50=32nM) and RTV (IC50=598nM) improved the effectiveness of 4DV3 (IC50=23μM) inhibition of HIV-1 replication. The stability of the ester drug conjugate was evaluated over time. Finally, third generation compounds were designed and synthesized to increase the drug loading. The studies that have been performed were designed to evaluate the potential of a targeted CXCR4 peptide carrier as a drug delivery system for HIV-1 therapy.
Subject
(authority = RUETD)
Topic
Pharmaceutical Science
RelatedItem
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TitleInfo
Title
Rutgers University Electronic Theses and Dissertations
Identifier
(type = RULIB)
ETD
Identifier
ETD_4514
PhysicalDescription
Form
(authority = gmd)
electronic resource
InternetMediaType
application/pdf
InternetMediaType
text/xml
Extent
xiv, 187 p. : ill.
Note
(type = degree)
Ph.D.
Note
(type = bibliography)
Includes bibliographical references
Note
(type = statement of responsibility)
by Matthew S. Palombo
Subject
(authority = ETD-LCSH)
Topic
Chemokines
Subject
(authority = ETD-LCSH)
Topic
HIV infections--Treatment
Subject
(authority = ETD-LCSH)
Topic
HIV (Viruses)
Subject
(authority = ETD-LCSH)
Topic
Peptide drugs--Dosage forms
Identifier
(type = hdl)
http://hdl.rutgers.edu/1782.1/rucore10001600001.ETD.000068930
RelatedItem
(type = host)
TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier
(type = local)
rucore19991600001
Location
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(displayLabel = Rutgers, The State University of New Jersey)
NjNbRU
Identifier
(type = doi)
doi:10.7282/T30V8BCT
Genre
(authority = ExL-Esploro)
ETD doctoral
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Rights
RightsDeclaration
(ID = rulibRdec0006)
The author owns the copyright to this work.
RightsHolder
(type = personal)
Name
FamilyName
Palombo
GivenName
Matthew
Role
Copyright Holder
RightsEvent
Type
Permission or license
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = start)
2013-03-27 14:56:17
AssociatedEntity
Name
Matthew Palombo
Role
Copyright holder
Affiliation
Rutgers University. Graduate School - New Brunswick
AssociatedObject
Type
License
Name
Author Agreement License
Detail
I hereby grant to the Rutgers University Libraries and to my school the non-exclusive right to archive, reproduce and distribute my thesis or dissertation, in whole or in part, and/or my abstract, in whole or in part, in and from an electronic format, subject to the release date subsequently stipulated in this submittal form and approved by my school. I represent and stipulate that the thesis or dissertation and its abstract are my original work, that they do not infringe or violate any rights of others, and that I make these grants as the sole owner of the rights to my thesis or dissertation and its abstract. I represent that I have obtained written permissions, when necessary, from the owner(s) of each third party copyrighted matter to be included in my thesis or dissertation and will supply copies of such upon request by my school. I acknowledge that RU ETD and my school will not distribute my thesis or dissertation or its abstract if, in their reasonable judgment, they believe all such rights have not been secured. I acknowledge that I retain ownership rights to the copyright of my work. I also retain the right to use all or part of this thesis or dissertation in future works, such as articles or books.
RightsEvent
DateTime
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(qualifier = exact);
(point = start)
2013-05-31
DateTime
(encoding = w3cdtf);
(qualifier = exact);
(point = end)
2015-05-31
Type
Embargo
Detail
Access to this PDF has been restricted at the author's request. It will be publicly available after May 31st, 2015.
Copyright
Status
Copyright protected
Availability
Status
Open
Reason
Permission or license
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Technical
RULTechMD
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ContentModel
ETD
OperatingSystem
(VERSION = 5.1)
windows xp
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