Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy
| Autor: | Julian Tirado-Rives, Raymond T. Chung, William L. Jorgensen, Todd J. Sullivan, Ebrahim Mohamed, Christopher M. Bailey, Pinar Iyidogan, Juliana Ruiz-Caro, Roger Hunter, Karen S. Anderson |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Anti-HIV Agents Oligonucleotides Virus Replication Article Mass Spectrometry Polyethylene Glycols Structure-Activity Relationship chemistry.chemical_compound X-Ray Diffraction Drug Discovery PEG ratio Humans Structure–activity relationship Bifunctional DNA Primers virus diseases Virology HIV Reverse Transcriptase In vitro Reverse transcriptase chemistry Viral replication Drug Design HIV-1 Reverse Transcriptase Inhibitors Molecular Medicine Indicators and Reagents Linker Nucleoside Dinucleoside Phosphates |
| Zdroj: | Journal of Medicinal Chemistry. 56:3959-3968 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm400160s |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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