Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

详细信息    查看全文

• 作者：Christopher M. Bailey ; Todd J. Sullivan ; Pinar Iyidogan ; Julian Tirado-Rives ; Raymond Chung ; Juliana Ruiz-Caro ; Ebrahim Mohamed ; William Jorgensen ; Roger Hunter ; Karen S. Anderson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：May 23, 2013
• 年：2013
• 卷：56
• 期：10
• 页码：3959-3968
• 全文大小：396K
• 年卷期：v.56,no.10(May 23, 2013)
• ISSN：1520-4804

文摘

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.