Abstract
Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / pharmacology*
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DNA Primers
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Dinucleoside Phosphates / chemistry
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Dinucleoside Phosphates / isolation & purification
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Drug Design
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HIV Reverse Transcriptase / chemistry
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HIV Reverse Transcriptase / isolation & purification
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HIV Reverse Transcriptase / metabolism
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HIV-1 / drug effects
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Humans
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Indicators and Reagents
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Mass Spectrometry
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Models, Molecular
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Oligonucleotides / chemistry
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Oligonucleotides / isolation & purification
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Polyethylene Glycols / pharmacology
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / pharmacology*
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Structure-Activity Relationship
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Virus Replication / drug effects
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X-Ray Diffraction
Substances
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Anti-HIV Agents
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DNA Primers
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Dinucleoside Phosphates
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Indicators and Reagents
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Oligonucleotides
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Reverse Transcriptase Inhibitors
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Polyethylene Glycols
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HIV Reverse Transcriptase