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The roles of structural variability and amphiphilicity of TMC278/rilpivirine in mechanisms of HIV drug resistance avoidance and enhanced oral bioavailability

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Text
TitleInfo (ID = T-1)
Title
The roles of structural variability and amphiphilicity of
TMC278/rilpivirine in mechanisms of HIV drug resistance avoidance and enhanced oral bioavailability
Identifier
ETD_1673
Identifier (type = hdl)
http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000051347
Language
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eng
Genre (authority = marcgt)
theses
Subject (ID = SBJ-1); (authority = RUETD)
Topic
Biochemistry
Subject (ID = SBJ-1); (authority = ETD-LCSH)
Topic
HIV (Viruses)
Subject (ID = SBJ-1); (authority = ETD-LCSH)
Topic
Drug resistance
Abstract
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are small hydrophobic drug molecules that bind to a hydrophobic pocket of the HIV-1 reverse transcriptase (RT). A number of molecules from diarylpyrimidine (DAPY) class of NNRTIs have exceptional inhibitory properties against a broad range of known drug-resistant viral strains of HIV-1 and good oral bioavailability in humans. Biophysical, structural, and computational methods were applied to study DAPY NNRTIs with differing RT inhibitory and bioavailability properties with a goal to define the mechanisms by which the dual success of the selected DAPY NNRTIs is achieved.
Exceptional bioavailability properties of selected DAPY NNRTIs were hypothesized to stem from their ability to form self-formulated spherical drug aggregates, ~60 nm in diameter, that are trafficked from the gastrointestinal tract into systemic circulation through a lymphatic uptake pathway. Using dynamic light scattering (DLS) and electron microscopy (EM), formation of drug aggregates was demonstrated. Drug aggregation was determined to be surfactant independent. Based on this observation, it was hypothesized that the drug molecules were able to achieve surface-active properties. Using X-ray crystallography and all atom MD simulations of the drug aggregate/water interface it was determined that amphiphilic properties of the selected DAPY NNRTI molecules depend on the availability of the protonation site at the pyrimidine ring and structural variability of the drug molecules at the linker moieties.
Ability of the late phase DAPY NNRTI drug molecules to inhibit the broad range of drug-resistant HIV-1 mutants has been previously linked to the ability of the molecules to sample multiple binding modes within the binding pocket of HIV-1 RT (Das et al., 2004). Using computational methods, conformational sampling by TMC278 (a DAPY NNRTI in multiple Phase III trials) in the pocket of the wild-type and the mutant NNRTI-binding pocket (NNIBP) was evaluated. Results of this work support the concept that structural variability is important in overcoming drug resistance mechanisms.
We propose that the implementation of drug aggregation testing and the evaluation of torsional flexibility of highly hydrophobic compounds in the context of the lead identification strategies will allow for better selection of potent and orally bioavailable hydrophobic drug candidates.
PhysicalDescription
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electronic resource
Extent
xiv, 148 p. : ill.
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application/pdf
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Note (type = degree)
Ph.D.
Note (type = bibliography)
Includes bibliographical references (139-146)
Note (type = statement of responsibility)
by Yulia Frenkel
Name (ID = NAME-1); (type = personal)
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Frenkel
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Yulia
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1979
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Yulia Frenkel
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Olson
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Wilma
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chair
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Advisory Committee
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Wilma Olson
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Arnold
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Eddy
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internal member
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Advisory Committee
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Eddy Arnold
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Stock
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Ann
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internal member
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Advisory Committee
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Ann Stock
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Levy
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Ronald
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Advisory Committee
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Ronald M Levy
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Gallicchio
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Emilio
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outside member
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Advisory Committee
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Emilio Gallicchio
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NamePart
Rutgers University
Role
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degree grantor
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NamePart
Graduate School - New Brunswick
Role
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school
OriginInfo
DateCreated (point = ); (qualifier = exact)
2009
DateOther (qualifier = exact); (type = degree)
2009-05
Place
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xx
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Title
Rutgers University Electronic Theses and Dissertations
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ETD
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TitleInfo
Title
Graduate School - New Brunswick Electronic Theses and Dissertations
Identifier (type = local)
rucore19991600001
Location
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NjNbRU
Identifier (type = doi)
doi:10.7282/T3HH6K98
Genre (authority = ExL-Esploro)
ETD doctoral
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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.
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