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J Med Chem. 2013 May 23;56(10):3959-68. doi: 10.1021/jm400160s. Epub 2013 May 9.

Bifunctional inhibition of human immunodeficiency virus type 1 reverse transcriptase: mechanism and proof-of-concept as a novel therapeutic design strategy.

Author information

1
Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.

Erratum in

  • J Med Chem. 2013 Nov 14;56(21):8953. Jorgensen, William [corrected to Jorgensen, William L].

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.

PMID:
23659183
PMCID:
PMC3733247
DOI:
10.1021/jm400160s
[Indexed for MEDLINE]
Free PMC Article

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